Chemical compounds

ABSTRACT

Benzimidazole derivatives, which are useful as TIE-2 and/or VEGFR2 inhibitors are described herein. The described invention also includes methods of making such benzimidazole derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US01/44553 filed Nov. 28, 2001, which claims priority from Ser. No.60/253,868 filed Nov. 29, 2000 and 60/310,939 filed Aug. 8, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to benzimidazole derivatives, compositionsand medicaments containing the same, as well as processes for thepreparation and use of such compounds, compositions and medicaments.Such benzimidazole derivatives are useful in the treatment of diseasesassociated with inappropriate or pathological angiogenesis.

The process of angiogenesis is the development of new blood vessels,generally capillaries, from pre-existing vasculature. Angiogenesis isdefined as involving (i) activation of endothelial cells; (ii) increasedvascular permeability; (iii) subsequent dissolution of the basementmembrane and extravisation of plasma components leading to formation ofa provisional fibrin gel extracellular matrix; (iv) proliferation andmobilization of endothelial cells; (v) reorganization of mobilizedendothelial cells to form functional capillaries; (vi) capillary loopformation; and (vii) deposition of basement membrane and recruitment ofperivascular cells to newly formed vessels. Normal angiogenesis isactivated during tissue growth, from embryonic development throughmaturity, and then enters a period of relative quiescence duringadulthood. Normal angiogensesis is also activated during wound healing,and at certain stages of the female reproductive cycle. Inappropriate orpathological angiogenesis has been associated with several diseasestates including various retinopathies; ischemic disease;atherosclerosis; chronic inflammatory disorders; and cancer. The role ofangiogenesis in disease states is discussed, for instance, in Fan et al,Trends in Pharmacol Sci. 16:5–66; Shawver et al, DDT Vol. 2, No. 2February 1997; Folkmann, 1995, Nature Medicine 1:27–31.

In cancer the growth of solid tumors has been shown to be angiogenesisdependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4–6.)Consequently, the targeting of pro-angiogenic pathways is a strategybeing widely pursued in order to provide new therapeutics in these areasof great, unmet medical need. The role of tyrosine kinases involved inangiogenesis and in the vascularization of solid tumors has drawninterest. Until recently most interest in this area has focused ongrowth factors such as vascular endothelial growth factor (VEGF) and itsreceptors termed vascular endothelial growth factor receptor(s) (VEGFR).VEGF, a polypeptide, is mitogenic for endothelial cells in vitro andstimulates angiogenic responses in vivo. VEGF has also been linked toinappropriate or pathological angiogenesis (Pinedo, H. M. et al. TheOncologist, Vol. 5, No. 90001, 1–2, April 2000). VEGFR(s) are proteintyrosine kinases (PTKs). PTKs catalyze the phosphorylation of specifictyrosyl residues in proteins involved in the regulation of cell growthand differentiation. (A. F. Wilks, Progress in Growth Factor Research,1990, 2, 97–111; S. A. Courtneidge, Dev. Supp.l, 1, 1993, 57–64; J. A.Cooper, Semin. Cell Biol., 1994, 5(6), 377–387; R. F. Paulson, Semin.Immunol., 1995, 7(4), 267–277; A. C. Chan, Curr. Opin. Immunol., 1996,8(3), 394–401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction (Mustonen, T. etal J. Cell Biol. 1995:129:895–898). Of particular interest is VEGFR-2,which is a transmembrane receptor PTK expressed primarily in endothelialcells. Activation of VEGFR-2 by VEGF is a critical step in the signaltransduction pathway that initiates tumor angiogenesis. VEGF expressionmay be constitutive to tumor cells and can also be upregulated inresponse to certain stimuli. One such stimuli is hypoxia, where VEGFexpression is upregulated in both tumor and associated host tissues. TheVEGF ligand activates VEGFR-2 by binding with its extracellular VEGFbinding site. This leads to receptor dimerization of VEGFRs andautophosphorylation of tyrosine residues at the intracellular kinasedomain of VEGFR-2. The kinase domain operates to transfer a phosphatefrom ATP to the tyrosine residues, thus providing binding sites forsignaling proteins downstream of VEGFR-2 leading ultimately toinitiation of angiogenesis (McMahon, G., The Oncologist, Vol. 5, No.90001, 3–10, April 2000).

Angiopoieten 1 (Ang1), a ligand for the endothelium-specific receptortyrosine kinase TIE-2 is a novel angiogenic factor (Davis et al, Cell,1996, 87:1161–1169; Partanen et al, Mol. Cell Biol, 12:1698–1707 (1992);U.S. Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831). Theacronym TIE represents “tyrosine kinase containing Ig and EGF homologydomains”. TIE is used to identify a class of receptor tyrosine kinases,which are exclusively expressed in vascular endothelial cells and earlyhemopoietic cells. Typically, TIE receptor kinases are characterized bythe presence of an EGF-like domain and an immunoglobulin (IG) likedomain, which consists of extracellular folding units, stabilized byintra-chain disulfide bonds (Partanen et al Curr. Topics Microbiol.Immunol., 1999, 237:159–172). Unlike VEGF, which functions during theearly stages of vascular development, Angi and its receptor TIE-2function in the later stages of vascular development, i.e., duringvascular remodeling (remodeling refers to formation of a vascular lumen)and maturation (Yancopoulos et al, Cell, 1998, 93:661–664; Peters, K.G., Circ. Res., 1998, 83(3):342–3; Suri et al, Cell 87, 1171–1180(1996)).

Consequently, inhibition of TIE-2 would be expected to serve to disruptremodeling and maturation of new vasculature initiated by angiogenesisthereby disrupting the angiogenic process. Furthermore, inhibition atthe kinase domain binding site of VEGFR-2 would block phosphorylation oftyrosine residues and serve to disrupt initiation of angiogenesis.Presumably then, inhibition of TIE-2 and/or VEGFR-2 should prevent tumorangiogenesis and serve to retard or eradicate tumor growth. Accordingly,a treatment for cancer or other disorder associated with inappropriateangiogenesis could be provided.

The present inventors have discovered novel benzimidazole compounds,which are inhibitors of TIE-2 and/or VEGFR-2 kinase activity. Suchbenzimidazole derivatives are useful in the treatment of disorders,including cancer, associated with inappropriate angiogenesis.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound ofFormula (I):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   E is aryl substituted by R¹ and R², or    -   unsubstituted heteroaryl, or    -   heteroaryl substituted with R¹, or    -   heteroaryl substituted by R¹ and R², or    -   R¹ and R² together with the atoms of E to which they are        attached form a cyloalkyl,    -   aryl, or heterocyclic ring fused to E;-   A is aryl, heteroaryl, or heterocyclic;-   X is S, O, S(O)₂, S(O), C(H)₂, C(H)(OH), or C(O);-   Z is O or S;-   p is 0 or 1;-   q is 0 or 1;-   the dotted line bonds “- - - ” attached to Q and N′ represent a    single bond or a double bond wherein when q is 0 the dotted line    bond “- - - ” attached to Q is a single bond and the dotted line    bond attached to N′ is a double bond, and when q is 1 the dotted    line bond “- - - ” attached to Q is a double bond and the dotted    line bond attached to N′ is a single bond; and-   the dotted line within the 6 membered ring containing D, M, and T    represents appropriate aromatic bonds;-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 0 and q    is 1; or-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 1 and q    is 0; or-   D is CH, T is CR⁸, M is C and Q is S or O; wherein q is 0;    -   D is N, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein either p or        q is 0 and the other is 1; or-   D is CH, T is Nn M is C and Q is N(R⁷)_(p), wherein either p or q is    0 and the other is 1; or-   D is CH, T is CR⁸, M is N and Q is CH, wherein q is 0;-   R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,    halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, aralkyl, aralkoxy, aryloxy,    C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆ alkylsulfonyl, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, cyanoalkyl;-   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy,    C₁–C₆ haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl,    C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, —NO₂,    —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, aralkoxy, heteroaryl,    heterocyclic, —RR⁶, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)RO    R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′ R⁶, —C(O)ROR′OR″O R⁶,    —C(O)ROR′O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶, —C(O)RNR⁴C(O)OR⁶,    —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or-   R³ is C₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is    linked together with the nitrogen to which it is attached and to one    of the benzimidazole nitrogens to form a heterocylic compound fused    to the benzimidazole;-   R, R′, and R″, are each independently selected from C₁–C₆ alkylene,    arylene, heteroarylene, C₃–C₇ cycloalkylene, or heterocyclylene;-   R′″ is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇cycloalkyl, or    heterocyclic;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁–C₆    alkyl, C₁–C₆ haloalkyl, C₁–C₆alkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic,    C₃–C₇cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH₂, or    —S(O)₂NR′″R′″;-   R⁶is hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl, aryl, heteroaryl,    aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;-   R⁷ is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶-   R⁸ is hydrogen or halogen; and    when R¹ is Cl, R² is hydrogen or Cl, R³ is —C(O)OCH₃, E and A are    phenyl, D is CH, T is CH, M is C, Q is N(R⁷)_(p), where R⁷ is H,    wherein either p or q is 0 and the other is 1, and Z is O, then X is    O, S(O), S(O)₂, CH2, CH(OH), or C(O).

In a second aspect of the present invention, there is provided acompound of Formula (I):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   E is unsubstituted heteroaryl, or    -   heteroaryl substituted with R¹, or    -   heteroaryl substituted by R¹ and R²;-   A is aryl, heteroaryl, or heterocyclic;-   X is S, O, S(O)₂, S(O), CH₂, CH(OH), or C(O);-   Z is O or S;-   p is 0 or 1;-   q is 0 or 1;-   the dotted line bonds “- - - ” attached to Q and N′ represent a    single bond or a double bond wherein when q is 0 the dotted line    bond “- - - ” attached to Q is a single bond and the dotted line    bond attached to N′ is a double bond, and when q is 1 the dotted    line bond “- - - ” attached to Q is a double bond and the dotted    line bond attached to N′ is a single bond; and-   the dotted line within the 6 membered ring containing D, M, and T    represents appropriate aromatic bonds;-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 0 and q    is 1; or-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 1 and q    is 0; or-   D is CH, T is CR⁸, M is C and Q is S or O; wherein q is 0;-   D is N, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein either p or q    is 0 and the other is 1; or-   D is CH, T is N, M is C and Q is N(R⁷)_(p), wherein either p or q is    0 and the other is 1; or-   D is CH, T is CR⁸, M is N and Q is CH, wherein q is 0;-   R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,    halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, aralkyl, aralkoxy, aryloxy,    C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfenyl,    C₁–C₆ alkylsulfonyl, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,    S(O)₂NR⁴R⁵, or cyanoalkyl;-   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy,    C₁–C₆ haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl,    C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, —NO₂,    —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, aralkoxy, heteroaryl,    heterocyclic, —RR₆, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)RO    R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′R⁶, —C(O)ROR′OR″O R⁶,    —C(O)ROR′O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶, —C(O)RNR⁴C(O)OR⁶,    —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or-   R³ is C₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is    linked together with the nitrogen to which it is attached and to one    of the benzimidazole nitrogens to form a heterocylic compound fused    to the benzimidazole;-   R, R′, and R″, are each independently selected from C₁–C₆ alkylene,    arylene, heteroarylene, C₃–C₇cycloalkylene, or heterocyclylene;-   R′″ is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇cycloalkyl, or    heterocyclic;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁–C₆    alkyl, C₁–C₆ haloalkyl, C₁–C₆alkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C₃–C₇    cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH₂, or    —S(O)₂NR′″R′″;-   R⁶is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;-   R⁷ is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶; and-   R⁸is hydrogen or halogen.

In a third aspect of the present invention, there is provided a compoundof Formula (II):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is aryl, heteroaryl, or heterocyclic;-   X is S, O, S(O)₂, S(O), CH₂, CH(OH), or C(O);-   Z is O or S;-   p is 0 or 1;-   q is 0 or 1;-   the dotted line bonds “- - - ” attached to Q and N′ represent a    single bond or a double bond wherein when q is 0 the dotted line    bond “- - - ” attached to Q is a single bond and the dotted line    bond attached to N′ is a double bond, and when q is 1 the dotted    line bond “- - - ” attached to Q is a double bond and the dotted    line bond attached to N′ is a single bond; and-   the dotted line within the 6 membered ring containing D, M, and T    represents appropriate aromatic bonds;-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 0 and q    is 1; or-   D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein p is 1 and q    is 0; or-   D is CH, T is CR⁸, M is C and Q is S or O; wherein q is 0;-   D is N, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein either p or q    is 0 and the other is 1; or-   D is CH, T is N, M is C and Q is N(R⁷)_(p), wherein either p or q is    0 and the other is 1; or-   D is CH, T is CR⁸, M is N and Q is CH, wherein q is 0;-   R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,    halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, aralkyl, aralkoxy, aryloxy,    C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfenyl,    C₁–C₆ alkylsulfonyl, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy,    C₁–C₆ haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl,    C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, —NO₂,    —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl; or-   R¹ and R²together with the phenyl ring atoms to which they are    attached form a cyloalkyl or aryl ring fused to the phenyl ring;-   R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, aralkoxy, heteroaryl,    heterocyclic, —RR⁶ ₁, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,    —C(O)RO R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′R⁶, —C(O)ROR′OR″O R⁶,    —C(O)ROR′O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶, —C(O)RNR⁴C(O)OR⁶,    —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or-   R³ is C₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is    linked together with the nitrogen to which it is attached and to one    of the benzimidazole nitrogens to form a heterocylic compound fused    to the benzimidazole;-   R, R′, and R″, are each independently selected from C₁–C₆ alkylene,    arylene, heteroarylene, C₃–C₇cycloalkylene, or heterocyclylene;-   R′″, is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇cycloalkyl, or    heterocyclic;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁–C₆    alkyl, C₁–C₆haloalkyl, C₁–C₆alkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C₃–C₇    cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH₂, or    —S(O)₂NR′″R′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;-   R⁷is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶-   R⁸ is hydrogen or halogen; and-   when R¹ is Cl, R² is H or Cl, R³ is —C(O)OCH₃, A is phenyl, D is CH,    T is CH, M is C and Q is N(R₇)_(p), where R⁷ is H, wherein either p    or q is 0 and the other is 1 and Z is O, then X is O, S(O), ═S(O)₂,    CH₂, CH(OH) or C(O).

In a fourth aspect of the present invention, there is provided acompound of Formula (III):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is aryl, heteroaryl, or heterocyclic;-   X is S, O, S(O)₂, S(O), CH₂, CH(OH), or C(O);-   Z is O or S;-   p is 0 or 1;-   q is 0 or 1, wherein either p or q is 0, and the other is 1;-   the dotted line bonds “- - - ” attached to N′ and N″ represent a    single bond or a double bond wherein when q is O the dotted line    bond “- - - ” attached to N′ is a single bond and the dotted line    bond attached to N″ is a double bond, and when q is 1 the dotted    line bond “- - - ” attached to N′ is a double bond and the dotted    line bond attached to N″ is a single bond;-   R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,    halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, aralkyl, aralkoxy, aryloxy,    C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfenyl,    C₁–C₆ alkylsulfonyl, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy,    C₁–C₆ haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl,    C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, —NO₂,    —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl; or-   R¹ and R²together with the phenyl ring atoms to which they are    attached form a cyloalkyl or aryl ring fused to the phenyl ring;-   R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, aralkoxy, heteroaryl,    heterocyclic, —RR⁶, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)RO    R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′R⁶, —C(O)ROR′OR″O R⁶,    —C(O)ROR′O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶, —C(O)RNR⁴C(O)OR⁶,    —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or-   R³ is C₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is    linked together with the nitrogen to which it is attached and to one    of the benzimidazole nitrogens to form a heterocylic compound fused    to the benzimidazole;-   R, R′, and R″, are each independently selected from C₁–C₆ alkylene,    arylene, heteroarylene, C₃–C₇cycloalkylene, or heterocyclylene;-   R′″is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇ cycloalkyl, or    heterocyclic;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁–C₆    alkyl, C₁–C₆haloalkyl, C₁–C₆alkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C₃–C₇    cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″; —C(O)NR′″H, —C(O)NH₂, or    —S(O)₂NR′″R′″;-   R⁶is hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl, aryl, heteroaryl,    aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;-   R⁷ is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶-   R⁸ is hydrogen or halogen; and-   when R¹ is Cl, R² is H or Cl, R³ is —C(O)OCH₃, A is phenyl, and Z is    O, then X is O, S(O), S(O)₂, CH₂, CH(OH), or C(O).

In a fifth aspect of the present invention, there is provided a compoundof formula (IV)

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   E is unsubstituted heteroaryl, or    -   heteroaryl substituted with R¹, or    -   heteroaryl substituted by R¹ and R²;-   A is aryl, heteroaryl, or heterocyclic;-   X is S, O, S(O)₂, S(O), CH₂, CH(OH), or C(O);-   Z is O or S;-   p is 0 or 1;-   q is 0 or 1;-   the dotted line bonds “- - - ” attached to N′ and N″ represent a    single bond or a double bond wherein when q is 0 the dotted line    bond “- - - ” attached to N′ is a single bond and the dotted line    bond attached to N″ is a double bond, and when q is 1 the dotted    line bond “- - - ” attached to N′ is a double bond and the dotted    line bond attached to N″ is a single bond;-   R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,    halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, aralkyl, aralkoxy, aryloxy,    C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfenyl,    C₁–C₆ alkylsulfonyl, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy,    C₁–C₆ haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl,    C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, —NO₂,    —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl;-   R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, aralkoxy, heteroaryl,    heterocyclic, —RR⁶, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)RO    R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′R⁶, —C(O)ROR′R″O R⁶,    —C(O)ROR″O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶, —C(O)RNR⁴C(O)OR⁶,    —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or-   R³ is C₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is    linked together with the nitrogen to which it is attached and to one    of the benzimidazole nitrogens to form a heterocylic compound fused    to the benzimidazole;-   R, R′, and R″, are each independently selected from C₁–C₆ alkylene,    arylene, heteroarylene, C₃–C₇cycloalkylene, or heterocyclylene;-   R′″ is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇ cycloalkyl, or    heterocyclic;-   R⁴ and R⁵ are each independently selected from hydrogen, C₁–C₆    alkyl, C₁–C₆ haloalkyl, C₁–C₆alkylsulfanyl, C₁–C₆alkylsulfenyl,    C₁–C₆alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C₃–C₇    cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH₂, or    —S(O)₂NR′″R′″;-   R⁶is hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl,    aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;-   R⁷ is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶; and-   R⁸is hydrogen or halogen.

In a sixth aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.

In a seventh aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate TIE-2 activity, including: administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate or a physiologically functional derivative thereof.

In an eighth aspect of the present invention, there is provided acompound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof for use in therapy.

In a ninth aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder mediated by inappropriate TIE-2 activity.

In a tenth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate TIE-2 activity, including: administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof and (ii)an agent to inhibit growth factor receptor function.

In an eleventh aspect of the present invention, there is provided amethod of treating a disorder in a mammal, said disorder beingcharacterized by inappropriate angiogenesis, including: administering tosaid mammal a therapeutically effective amount of a compound of formula(I), or a salt, solvate or physiologically functional derivativethereof.

DETAILED DESCRIPTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting ofC₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl,C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or C₁–C₆ perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkyl” as used herein include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, and the like.

As used herein, the term “C₁–C₆ alkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atoms.Examples of branched or straight chained “C₁–C₆ alkyl” groups useful inthe present invention include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, andisopentyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the term “C₁–C₆ alkylene” refers to an alkylene group,as defined above, which contains at least 1, and at most 6, carbon atomsrespectively. Examples of “C₁–C₆ alkylene” groups useful in the presentinvention include, but are not limited to, methylene, ethylene, andn-propylene.

As used herein, the term “halogen” refers to fluorine (F), chlorine(Cl), bromine (Br), or iodine (I).

As used herein, the term “C₁–C₆ haloalkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atomssubstituted with at least one halogen, halogen being as defined herein.Examples of branched or straight chained “C₁–C₆ haloalkyl” groups usefulin the present invention include, but are not limited to, methyl, ethyl,propyl, isopropyl, isobutyl and n-butyl substituted independently withone or more halogens, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term “C₃–C₇ cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven carbon atoms andwhich optionally includes a C₁–C₆ alkyl linker through which it may beattached. The C₁–C₆ alkyl group is as defined above. Exemplary “C₃–C₇cycloalkyl” groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “C₃–C₇ cycloalkylene” refers to a non-aromaticalicyclic divalent hydrocarbon radical having from three to seven carbonatoms, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring having one ormore degrees of unsaturation containing one or more heteroatomicsubstitutions selected from S, SO, SO₂, O, or N, optionally substitutedwith substituents selected from the group consisting of C₁–C₆ alkyl,C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆haloalkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or C₁–C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Such a ring may beoptionally fused to one or more other “heterocyclic” ring(s) orcycloalkyl ring(s). Examples of “heterocyclic” moieties include, but arenot limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane,piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical having one or more degreesof unsaturation containing one or more heteroatoms selected from S, SO,SO₂, O, or N, optionally substituted with substituents selected from thegroup which includes lower alkyl lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings to form, forexample, anthracene, phenanthrene, or napthalene ring systems. Exemplaryoptional substituents include C₁–C₆ alkyl C₁–C₆ alkoxy, C₁–C₆alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁–C₆perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “aryl” groups include, but are not limitedto, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substitutedderivatives thereof.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group which includes lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through a C₁–C₆ alkyl linker, whereinC₁–C₆ alkyl is as defined herein. Examples of “aralkyl” include, but arenot limited to, benzyl, phenylpropyl, 2-pyridylmethyl,3-isoxazolylmethyl, 5-methyl, 3-isoxazolylmethyl, and 2-imidazoylyethyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxidesare permissible heteroatom substitutions and may be optionallysubstituted with up to three members selected from a group consisting ofC₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆haloalkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁–C₆perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “heteroaryl” groups used herein includefuranyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl,thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl,indazolyl, and substituted versions thereof.

As used herein, the term “heteroarylene” refers to a five—toseven—membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting of:lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “alkoxy” refers to the group RO—, where R_(a)is alkyl as defined above and the term “C₁–C₆ alkoxy” refers to analkoxy group as defined herein wherein the alkyl moiety contains atleast 1, and at most 6, carbon atoms. Exemplary C₁–C₆ alkoxy groupsuseful in the present invention include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the term “C₁–C₆ haloalkoxy”refers to an haloalkoxy group as defined herein wherein the haloalkylmoiety contains at least 1, and at most 6, carbon atoms. Exemplary C₁–C₆haloalkoxy groups useful in the present invention include, but are notlimited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, andt-butoxy substituted with one or more halo groups, for instancetrifluoromethoxy.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkyl and R_(b) is aryl as defined above.

As used herein the term “aryloxy” refers to the group R_(a)O—, whereR_(a) is aryl as defined above.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above and the term “C₁–C₆alkylsulfanyl”refers to an alkylsulfanyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “haloalkylsulfanyl” refers to the groupR_(a)S—, where R_(a) is haloalkyl as defined above and the term “C₁–C₆haloalkylsulfanyl” refers to a haloalkylsulfanyl group as defined hereinwherein the alkyl moiety contains at least 1, and at most 6, carbonatoms.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above and the term “C₁–C₆alkylsulfenyl”refers to an alkylsulfenyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl as defined above and the term “C₁–C₆ alkylsulfonyl”refers to an alkylsulfonyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “oxo” refers to the group ═O

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “carboxy” refers to the group —COOH.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —CNR_(a),wherein R_(a) is alkyl as defined above. Exemplary “cyanoalkyl” groupsuseful in the present invention include, but are not limited to,cyanomethyl, cyanoethyl, and cyanoisopropyl.

As used herein, the term “aminosulfonyl” refers to the group —SO₂NH₂.

As used herein, the term “carbamoyl” refers to the group —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂—.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or formula (II) or a salt or physiologically functionalderivative thereof) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Examples of suitable solvents include, but are not limited to, water,methanol, ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers.Accordingly, the compounds of this invention include mixtures ofenantiomers as well as purified enantiomers or enantiomerically enrichedmixtures. Also included within the scope of the invention are theindividual isomers of the compounds represented by formulae (I) and (II)above as well as any wholly or partially equilibrated mixtures thereof.The present invention also covers the individual isomers of thecompounds represented by the formulas above as mixtures with isomersthereof in which one or more chiral centers are inverted. Also, it isunderstood that all tautomers and mixtures of tautomers of the compoundsof formulae (I) or (II) are included within the scope of the compoundsof formulae (I) and (II).

It is to be understood that reference to compounds of formula (I) andformula (II) above, following herein, refers to compounds within thescope of formula (I) and formula (II) as defined above with respect toE, X, Z, A, D, M, T, Q, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ unlessspecifically limited otherwise. It is also understood that the followingembodiments, including uses and compositions, although recited withrespect to formula (I) are also applicable to formulae (II), (III), and(IV).

In one embodiment, E is aryl substituted with R¹ and R². In a preferredembodiment, E is phenyl substituted with R¹ and R². In anotherembodiment, E is unsubstituted heteroaryl, heteroaryl substituted withR¹, or heteroaryl substituted with R¹ and R². In a preferred embodiment,E is heteroaryl substituted with R¹ or heteroaryl substituted with R¹and R². In a more preferred embodiment, E is heteroaryl substituted withR¹, wherein R¹ is preferably C₁–C₆ alkyl, more preferably —C(CH₃)₃, i.e.tert-butyl. In another preferred embodiment, E is selected from

either unsubstituted, substituted by R¹ or substituted by R¹ and R².

It is understood that E is attached to the indicated linking group ofFormula (I) through the bond of E having an unfilled valence and beingindicated by

The appropriate attachments are further illustrated in the workingexamples recited below.

In another embodiment, E is phenyl and R¹ and R² together with thephenyl ring atoms with which they are attached form a cycloalkyl,preferably cyclopentyl, or aryl, preferably phenyl fused to E.

In one embodiment, the compound of formula (I) is a compound of formula

or salt, solvate, or physiologically functional derivative thereof.

In one embodiment, the compound of formula (I) is a compound of formula(IV):

wherein E is unsubstituted heteroaryl, heteroaryl substituted with R¹,or heteroaryl substituted with R¹ and R², or a salt, solvate, orphysiologically functional derivative thereof.

In one embodiment, R¹ is C₁–C₆ alkyl, C₁–C₆ alkoxy, aryloxy, C₁–C₆haloalkyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfanyl, —C(O)OR⁶,halogen, —CN, or —NO₂. In a preferred embodiment, R¹ is C₁–C₆ alkyl,C₁–C₆haloalkyl, C₁–C₆ alkoxy, —NO₂, or halogen. In a more preferredembodiment, R¹ is —NO₂, —OCH₃, —CH₂CH₃, —C(CH₃)₃,—CF₃, —F, —Cl, and —Br.In another preferred embodiment, R¹ is C₁–C₆ haloalkyl, preferably —CF₃.In still another preferred embodiment, R¹ is C₁–C₆alkyl, preferably—C(CH₃)₃.

In one embodiment, R² is hydrogen, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy,or C₁–C₆ haloalkyl. In a preferred embodiment, R² is hydrogen orhalogen. In a more preferred embodiment, R² is hydrogen, —F, —Cl, or—Br. In a most preferred embodiment, R² is fluorine.

In one embodiment, R¹ is C₁–C₆ alkyl, C₁–C₆ alkoxy, aryloxy, C₁–C₆haloalkyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆alkylsulfanyl, —C(O)OR⁶,halogen, —CN, or NO₂and R² is hydrogen, halogen, C₁–C₆ alkyl, C₁–C₆alkoxy, or C₁–C₆ haloalkyl. In a preferred embodiment, R¹ is C₁–C₆haloalkyl and R² is hydrogen or halogen. In a more preferred embodiment,R¹ is NO₂, —OCH₃, —CH₂CH₃, —C(CH₃)₃, —CF₃, —F, —Cl, and —Br and R² ishydrogen, —F, —Cl, or —Br. In a most preferred embodiment, R¹ is —CF₃and R² is fluorine.

In one embodiment Z is S or O. In one embodiment, Z is S. In a preferredembodiment, Z is O.

In one embodiment, A is aryl or heteroaryl. In a preferred embodiment, Ais phenyl, 2-pyridyl or 3-pyridyl. In a more preferred embodiment A isphenyl.

In one embodiment, X is S, O, S(O)₂, S(O), CH₂, CH(OH), or C(O). In apreferred embodiment, X is O or C(O). In a more preferred embodiment, Xis O. In another embodiment, X is S.

The side chain —NHC(Z)NHE of the compounds of formula (I) and formula(II) may be linked to any suitable position of the group A. Similarly,the linker group X linking the benzimidazole core to the group A may belinked to any suitable position of the group A. Preferably the group Ais linked to the side chain —NHC(Z)NHE and to the linker group X of thebenzimidazole core through a (-1,3-) or (-1,4) linkage. In one preferredembodiment, the group A is linked through a (-1,4-) linkage. In anotherpreferred embodiment, the group A is linked through a (-1,3-) linkage.

The two dotted line bonds represented by “---”, which are attached to Qand N′ in the five-membered heterocyclic core of Formula I, mayrepresent a single bond or a double bond. When q is 0, the dotted linebond “---” attached to Q is a single bond and the dotted line bondattached to N′ is a double bond as illustrated following:

When q is 1, the dotted line bond “---” attached to Q is a double bondand the dotted line bond attached to N′ is a single bond as illustratedfollowing:

The dotted line within the 6 membered ring containing D, M, and T ofFormula I, represents the appropriate aromatic bonds.

In a preferred embodiment, D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p),wherein p is 0, q is 1, R⁷ is hydrogen, methyl, or S(O)₂R⁶ or D is CH, Tis CR⁸, wherein R⁸ is hydrogen or —Br, M is C and Q is N(R⁷)_(p),wherein p is 1, q is 0, R⁷ is hydrogen, methyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶ or aralkyl. In a more preferred embodiment, D is CH, T is CR⁸,wherein R⁸ is hydrogen, M is C and Q is N(R⁷)_(p), wherein either p or qis 0, the other is 1 and R⁷ is hydrogen.

In another embodiment, D is CH, T is CR⁸, wherein R⁸ is hydrogen or —Br,M is C and Q is S or O; wherein q is 0. In a further embodiment, D is N,T is CR⁸, wherein R⁸ is hydrogen or —Br, M is C and Q is N(R⁷)_(p),wherein either p or q is 0, the other is 1, R⁷ is hydrogen, methyl, orS(O)₂R⁶. In an alternative embodiment, D is CH, T is N, M is C and Q isN(R⁷)_(p), wherein either p or q is 0, the other is 1, R⁷ is hydrogen,methyl, or S(O)₂R⁶. In a further alternative embodiment, D is CH, T isCR⁸, wherein R⁸ is hydrogen or —Br, M is N and Q is CH, wherein q is 0.

In one embodiment, R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)ROR⁶,—C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵; In a preferredembodiment, R³ is —C(O)R⁶, —C(O)NR⁴R⁵, or —C(O)OR⁶. In a more preferredembodiment, R³ is —C(O)OR⁶. In a most preferred embodiment, R³is—C(O)OR⁶ and R⁶ is methyl.

In one embodiment, A is phenyl; X is O; Z is O; R¹ is C₁–C₆alkyl,C₁–C₆alkoxy, C₁–C₆ haloalkyl, or NO₂; R² is hydrogen, halogen, C₁–C₆alkyl, or C₁–C₆alkoxy; and R³ is —C(O)R, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵. In a preferredembodiment, A is phenyl; X is O; Z is O; R¹ is C₁–C₆ alkyl or C₁–C₆haloalkyl; R² is hydrogen or halogen; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, or—C(O)OR⁶. In a more preferred embodiment, A is phenyl; X is O; Z is O;R¹ is C₁–C₆ haloalkyl; R² is halogen; and R³ is —C(O)OR⁶.

In one embodiment, A is phenyl; X is S; Z is O; R¹ is C₁–C₆alkyl,C₁–C₆alkoxy, C₁–C₆ haloalkyl, or NO₂; R² is hydrogen, halogen, C₁–C₆alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″O R⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵. In a preferredembodiment, A is phenyl; X is S; Z is O; R¹ is C₁–C₆alkyl or C₁–C₆haloalkyl; R² is hydrogen or halogen; and R³ is —C(O)R⁶ or —C(O)OR⁶. Ina more preferred embodiment, A is phenyl; X is S; Z is O; R¹ is C₁–C₆haloalkyl; R² is halogen; and R³ is —C(O)OR⁶.

In one embodiment, A is pyridyl; X is O; Z is O; R¹ is C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ haloalkyl, or NO₂; R² is hydrogen, halogen, C₁–C₆alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R,⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵. In a preferredembodiment, A is pyridyl; X is O; Z is O; R¹ is C₁–C₆ alkyl or C₁–C₆haloalkyl; R² is hydrogen or halogen; and R³ is —C(O)R⁶ or —C(O)OR⁶. Ina more preferred embodiment, A is pyridyl; X is O; Z is O; R¹ is C₁–C₆haloalkyl; R² is halogen; and R³ is —C(O)OR⁶.

In one embodiment, A is pyridyl; X is S; Z is O; R¹ is C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ haloalkyl, or NO₂; R² is hydrogen, halogen, C₁–C₆alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶ —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR″, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵. In a preferredembodiment, A is pyridyl; X is S; Z is O; R¹ is C₁–C₆ alkyl or C₁–C₆haloalkyl; R² is hydrogen or halogen; and R³ is —C(O)R⁶ or —C(O)OR⁶. Ina more preferred embodiment, A is pyridyl; X is S; Z is O; R¹ is C₁–C₆haloalkyl; R² is halogen; and R³ is —C(O)OR⁶.

In one embodiment, the compound is a compound of formula (IV) where E isunsubstituted heteroaryl, heteroaryl substituted by R¹, or heteroarylsubstituted by R¹ and R², A is phenyl; X is O; Z is O; R¹ is C₁–C₆alkyl, aryl, C₃–C₇cycloalkyl, heterocyclyl, C₁–C₆haloalkyl, or C₁–C₆alkylsulfanyl; R² is hydrogen, halogen, C₁–C₆alkyl, or C₁–C₆haloalkyl;and R³ is —C(O)R, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)ROR⁶, —C(O)RC(O)OR⁶,—C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O)R⁶,—C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵. In a preferred embodiment, E isheteroaryl substituted by R¹ or heteroaryl substituted by R¹ and R², Ais phenyl; X is O; Z is O; R¹ is C₁–C₆ alkyl; R² is hydrogen or halogen;and R³ is —C(O)R⁶, —C(O)ROR′OR⁶, or —C(O)OR⁶. In a more preferredembodiment, E is heteroaryl substituted by R¹, A is phenyl; X is O; Z isO; R¹ is —C(CH₃)₃; and R³ is —C(O)R⁶.

Specific examples of compounds of the present invention include thefollowing:

-   Methyl    N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)    phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;-   Methyl    (5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Ethyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   T-butyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   2-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;-   (6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;-   6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)cyclopentamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylpentamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-acetylamino)acetamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-aminoacetamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-methoxyacetamide;-   3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionic    acid;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;-   N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide;-   Methyl    N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    and-   Methyl    N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    or a salt, solvate, or physiologically functional derivative    thereof.

Further specific Examples of compounds of the present invention include:

-   Methyl    N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamate;-   Methyl    N-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamate;-   Methyl    N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3a-aza-2-indolyl)carbamate;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diazaindolin-2-yl)carbamate;-   Methyl    N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate-   Methyl    N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;-   Methyl    N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;-   Methyl    N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;-   Methyl    N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamate;-   6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a,5-triazacarbazol-2-one;-   Methyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcarbonyl)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;-   2-(Dimethylamino)ethyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Benzyl    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)methanesulfonamide;-   5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylbenzenesulfonamide;-   N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)methanesulfonamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-5-benzimidazolecarboxamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(dimethylamino)butylamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-pyridinecarboxamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-tetrahydrofurancarboxamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-indole-3-carboxamide);-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-imidazole-4-carboxamide);-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)benzamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-thiophenecarboxamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide;-   N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(dimethylamino)acetamide;-   6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;-   7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;-   2-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;-   2-(2-(Dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;-   2-(3-(4-Methyl-1-piperazino)propylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;-   Methyl    N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;-   N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide;-   Methyl    N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;-   6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine;-   N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide;    and-   Methyl    N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzoxazol-2-yl)carbamate;    or a salt, solvate, or physiologically functional derivative    thereof.

Additional further specific Examples of compounds of the presentinvention include:

-   Methyl    N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    Methyl    N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;-   1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea;-   1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-4-(N,N    dimethylamino)phenyl)urea;-   1-(6-(4-((4Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea;-   1-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea;-   N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-(Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((4-tert-Butyl-thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((1,3,4Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((4-tert-Butyl-thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-tert-Butyl    1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((4,5-Dimetylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2furyl)formamide;-   N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2furyl)formamide;-   N-(5-(4-((5-Cycloproyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-(5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;-   N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;-   N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;-   Methyl    N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea;-   Methyl    N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;-   Methyl    N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    and-   Methyl    N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    or a salt, solvate, or physiologically functional derivative    thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to. non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I). Representative salts include the followingsalts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of the formula (I) and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula (I), or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, orpolyethyleneoxidepolylysine substituted with palmitoyl residues.Furthermore, the compounds may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian However, an effective amount of acompound of formula (I) for the treatment of neoplastic growth, forexample colon or breast carcinoma, will generally be in the range of 0.1to 100 mg/kg body weight of recipient (mammal) per day and more usuallyin the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or more usuallyin a number (such as two, three, four, five or six) of sub-doses per daysuch that the total daily dose is the same. An effective amount of asalt or solvate, or physiologically functional derivative thereof, maybe determined as a proportion of the effective amount of the compound offormula (I) per se. It is envisaged that similar dosages would beappropriate for treatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in anti-cancer therapy,combination with other chemotherapeutic, hormonal or antibody agents isenvisaged as well as combination with surgical therapy and radiotherapy.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof, or a physiologically functional derivative thereof,and at least one other pharmaceutically active agent, preferably ananti-neoplastic agent. The compound(s) of formula (I) and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and at least one additional cancertreatment therapy may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination with suchother anti-cancer therapies. In one embodiment, the other anti-cancertherapy is at least one additional chemotherapeutic therapy includingadministration of at least one anti-neoplastic agent. The administrationin combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives thereof with otheranti-neoplastic agents may be in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one anti-neoplastic agent is administeredfirst and the other second or vice versa. Such sequential administrationmay be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts, solvates or physiologically functional derivatives thereof offormula I include the following:

(1) cell cycle specific anti-neoplastic agents include, but are notlimited to diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine;antimetabolites such as allopurinol, fludurabine, methotrexate,cladrabine, cytarabine, mercaptopurine and thioguanine; andcamptothecins such as 9-amino camptothecin, irinotecan, CPT-11 and thevarious optical forms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumour antibiotics such as doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin andmithramycin; and platinum coordination complexes such as cisplatin,carboplatin, and oxaliplatin; and

(3) other chemotherapeutic agents include, but are not limited to,anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifeneand iodoxyfene; progestrogens such as megestrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamide, bicalutamide, andcyproterone acetate; LHRH agonists and antagagonists such as goserelinacetate and luprolide, testosterone 5α-dihydroreductase inhibitors suchas finasteride; metalloproteinase inhibitors such as marimastat;antiprogestogens; urokinase plasminogen activator receptor functioninhibitors; growth factor function inhibitors such as inhibitors of thefunctions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growthfactor receptor (EGFR), platelet derived growth factor receptor (PDGFR),vascular endothelial growth factor receptor (VEGFR, and TIE-2 (otherthan those VEGFR and TIE-2 inhibitors described in the presentinvention); and other tyrosine kinase inhibitors such as inhibitors ofCDK2 and CDK4 inhibitors.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are believed to have anticancer activityas a result of inhibition of the protein kinase TIE-2 and its effect onselected cell lines whose growth is dependent on TIE-2 protein kinaseactivity.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated byinappropriate TIE-2 activity.

The inappropriate TIE-2 activity referred to herein is any TIE-2activity that deviates from the normal TIE-2 activity expected in aparticular mammalian subject. Inappropriate TIE-2 activity may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of TIE-2 activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation. Furthermore, it is also understood thatunwanted TIE-2 activity may reside in an abnormal source, such as amalignancy. That is, the level of TIE-2 activity does not have to beabnormal to be considered inappropriate, rather the activity derivesfrom an abnormal source. In a like manner, the inappropriateangiogenesis referred to herein is any angiogenic activity that deviatesfrom the normal angiogenic activity expected in a particular mammaliansubject Inappropriate angiogenesis may take the form of, for instance,an abnormal increase in activity, or an aberration in the timing and orcontrol of angiogenic activity. Such inappropriate activity may resultthen, for example, from overexpression or mutation of a protein kinaseleading to inappropriate or uncontrolled activation. Furthermore, it isalso understood that unwanted angiogenic activity may reside in anabnormal source, such as a malignancy. That is, the level of angiogenicactivity does not have to be abnormal to be considered inappropriate,rather the activity derives from an abnormal source.

The present invention is directed to methods of regulating, modulating,or inhibiting TIE-2 for the prevention and/or treatment of disordersrelated to unregulated TIE-2 activity. In particular, the compounds ofthe present invention can also be used in the treatment of certain formsof cancer. Furthermore, the compounds of the present invention can beused to provide additive or synergistic effects with certain existingcancer chemotherapies, and/or be used to restore effectiveness ofcertain existing cancer chemotherapies and radiation.

The compounds of the present invention are also useful in the treatmentof one or more diseases afflicting mammals which are characterized bycellular proliferation in the area of disorders associated withneo-vascularization and/or vascular permeability including blood vesselproliferative disorders including arthritis and restenosis; fibroticdisorders including hepatic cirrhosis and atherosclerosis; mesangialcell proliferative disorders include glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, organ transplant rejection and glomerulopathies; andmetabolic disorders include psoriasis, diabetes mellitus, chronic woundhealing, inflammation and neurodegenerative diseases.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by inappropriate TIE-2activity, including susceptible malignancies, which includesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt, solvate, or aphysiologically functional derivative thereof. In a preferredembodiment, the disorder is cancer.

A further aspect of the invention provides a method of treatment of amammal suffering from cancer which includes administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by inappropriate TIE-2 activity. In a preferredembodiment, the disorder is cancer.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of cancer and malignanttumors.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

In another embodiment, therapeutically effective amounts of thecompounds of formula (I) or salts, solvates or physiologically derivedderivatives thereof and agents which inhibit growth factor receptorfunction may be administered in combination to a mammal for treatment ofa disorder mediated by inappropriate TIE-2 activity, for instance in thetreatment of cancer. Such growth factor receptors include, for example,EGFR, PDGFR, erbB2, erbB4, VEGFR, and/or TIE-2. Growth factor receptorsand agents that inhibit growth factor receptor function are described,for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000)10(6):803–818 and in Shawver et al DDT Vol 2, No. 2 February 1997.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and the agent for inhibiting growthfactor receptor function may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination. Thecombination may be employed in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one is administered first and the other secondor vice versa. Such sequential administration may be close in time orremote in time.

In another aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate angiogenesis, including: administering to said mammal atherapeutically effective amount of a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof. In oneembodiment, the inappropriate angiogenic activity is due to at least oneof inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity. In anotherembodiment, the inappropriate angiogenesis is due to inappropriateVEGFR2 and TIE-2 activity. In a further embodiment, the method furtherincludes administering a therapeutically effective amount of a VEGFR2inhibitor along with the compounds of formula (I) or salts, solvates orphysiologically functional derivatives thereof. Preferably the disorderis cancer.

In another aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate or physiologicallyfunctional derivative thereof in the preparation of a medicament for usein treating a disorder in a mammal, said disorder being characterized byinappropriate angiogenesis. In one embodiment, the inappropriateangiogenic activity is due to at least one of inappropriate VEGFR1,VEGFR2, VEGFR3 or TIE-2 activity. In another embodiment, theinappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2activity. In a further embodiment, the use further includes use of aVEGFR2 inhibitor to prepare said medicament.

The combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives thereof with a VEGFR2 inhibitormay be employed in combination in accordance with the invention byadministration concomitantly in (1) a unitary pharmaceutical compositionincluding both compounds or (2) separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein one isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the WorkingExamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of Formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of Formula (I), wherein R³ is —C(O)OCH₃, A is phenyl, and Xand Z are oxygen, D and T are CH, M is C, Q is N(R⁷)_(p), either p or qis 1, and the other is 0, can be prepared according to the syntheticsequence shown in Scheme 1 and further detailed in the Examples sectionfollowing. 4-Acetamidophenol (1) in DMF is reacted with5-chloro-2-nitroaniline (2) in the presence of 60% NaH to provide5-(4-acetamidophenoxy)-2-nitroaniline (3). The nitroaniline (3) is thenrefluxed with Na₂S₂O₄ to provide4-(4-acetamidophenoxy)phenylene-1,2-diamine (4). (It is understood thatreduction of nitro group of (3) can be effected in many ways, forexample by use of H₂, Pd/C; Raney Nickel with hydrazine; SnCl₄ in HCl;etc.) Diamine (4) is refluxed with1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and theacetylated carbamate (5) is obtained. HCl is added to deacetylate thecarbamate (5) to give methyl(5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7). Alternatively,carbamate (7) may be prepared by refluxing 3,4,4′-triaminodiphenylether(6) with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and thentreating with conc. HCl to give carbamate (7). Carbamate (7) is thenreacted with the appropriate phenyl isocyanate (8) to give the resultantbenzimidazole (9) of the present invention. It is understood that R¹ andR² are as described above. When X of Formula (I) is sulfur and Z ofFormula (I) is oxygen, the final compounds are obtained by following thesame procedure using a phenylthiol derivative of 1. When X of Formula(I) is sulfur, the compound thus obtained can be oxidized with MCPBA(metachloroperbenzoic acid) to give compounds containing sulfone (SO₂)or sulfine (SO) as X. Also, when3-(3-substitutedphenyl)aminocarbonylamino)phenoxy derivatives of Formula1 are prepared, 3-acetamidophenol is utilized instead of4-acetamidophenol.

Compounds of Formula (I), wherein A is phenyl, X and Z are oxygen, D andT are CH, M is C, Q is N(R⁷)_(p), either p or q is 1, and the other isO, R¹ is CF₃, R² is F, and R³ is a substituted carbonyl, can be preparedaccording to the synthetic sequence shown in Scheme 2 and furtherdetailed in the Examples section following. 4-aminophenol (1) in DMF isreacted with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH togive 5-(4-aminophenoxy)-2-nitroaniline (3). The compound (3) is reactedwith 2-fluoro-5-trifluoromethylphenylisocyanate (4) to provide5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline(5). The nitroaniline (5) is hydrogenated under an H₂ atmosphere in thepresence of Pd/C to give the corresponding diamine (6). Diamine (6) isreacted with cyanogen bromide to give benzimidazole (7). Benzimidazole(7) may be reacted with the appropriate carboxylic acid in the presenceof triethylamine and HBTU(O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate)to give the corresponding benzimidazole (8). Benzimidazole (7) may alsobe reacted with J′SO₂Cl (J′ is methyl or p-tolyl) to give a couple ofendo-sulfonated products (9, 10). J′SO₂ moiety was migrated to the exosite by heating (11). Further, benzimidazole (7) may be reacted withisocyanate J″NCO to give diurea (12). When X of Formula (I) is sulfurand Z of Formula (I) is oxygen, the final compounds are obtained byfollowing the same procedure except that a phenylthiol derivative of 1is used. When X of Formula (I) is sulfur, the compound thus obtained canbe oxidized with MCPBA (meta-chloroperbenzoic acid) to give compoundscontaining sulfonyl (—SO₂) or sulfenyl (—SO) as X. Also, as indicatedabove 3-(3-substituted phenyl)aminocarbonylamino)phenoxy derivatives ofFormula 1 are prepared using 3-acetamidophenol instead of4-acetamidophenol. The substituent J may be any substituent attached toC(O) within the scope of the definition of R³ as recited herein. Thesubstituent J″ may be any substituent R⁵ as defined herein.

Compounds of Formula I, wherein A is pyridyl, D and T are CH, M is C, Qis N(R⁷)_(p), either p or q is 1, and the other is 0, can be preparedaccording to the synthetic sequence shown in Scheme 3 and furtherdetailed in the Examples section following. The terms A1 and A2 refer toN and C, or C and N, respectively. 5-Hydroxybenzimdazole derivative (2)with or without a protecting group L is coupled with halonitropyridine(1) in the presence of base e.g. Cs₂CO₃ to give compound (3). Subsequenthydrogenation over Pd-C provides aniline derivative (4), followed bycoupling with isocyanate (and deprotection if needed) to afford urea(5). ). The intermediate (4) can also be provided by way of triamine(6).

Compounds of Formula I, wherein D is CH, T is C, M is C, Q is N(R⁷)_(p),R⁷ is CH₃, p is 0 and q is 1, can be prepared according to the syntheticsequence shown in Scheme 4 and further detailed in the Examples sectionfollowing. 4-(4-Nitrophenoxy)-2-nitroaniline (1) was coupled with1-fluoro-4-nitrobenzene with NaH to give (2). Methylation, hydrogenationproceeding through (3), and subsequent cyclization with (4) afforded(5), followed by coupling with isocyanate (6) to yield urea (7).

Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is N(R⁷)_(p)(p is 1; R⁷ is C₁–C₆ alkyl, —RNR⁴R⁵ or —RR⁶), and q is 0, can beprepared according to the synthetic sequence shown in Scheme 5 andfurther detailed in the Examples section following.N-alkyl-5-chloro-2-nitroaniline (3), derived from (1) or (2), wascoupled with 4-aminophenol to provide (4). Using methods similar tothose shown in the previous Schemes, hydrogenation, cyclization through(5), and coupling with isocyanate afforded (6).

Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is O, and qis 0,can be prepared according to the synthetic sequence shown in Scheme6 and further detailed in the Examples section following. 4-Aminophenol(1) was coupled with (2) to give ether (3), which was coupled withisocyante to afford (4). Hydrogenation and cyclization with BrCN to give(5), followed by the reaction with ClCOOMe gave oxazole derivative (6).

Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is S, and qis 0, can be prepared according to the synthetic sequence shown inScheme 7 and further detailed in the Examples section following.4-(4-Nitrophenoxy)aniline (2), derived from (1) and 4-aminophenol, wascyclized with KSCN and Br₂ in the presence of acid to provide thiazole(3). Subsequent reaction with ClCO₂Me or butylisocyante (BuNCO) to give(4), followed by reduction with SnCl₂ to give (5) and finally couplingwith isocyanate afforded (6).

Compounds of Formula I, wherein D is N, T is CH, M is C, Q is N(R⁷)_(p),R⁷ is H, either p or q is 1, and the other is 0, can be preparedaccording to the synthetic sequence shown in Scheme 8 and furtherdetailed in the Examples section following.2-Amino-6-chloro-3-nitropyridine (1) was coupled with4-acetylaminophenol (2) with K₂CO₃ to provide ether (3). Using methodssimilar to those shown in the previous Schemes, hydrogenation andcyclization to give (4), hydrolysis to give (5), and coupling withisocyanate, were carried out to yield pyridoimidazole (6).

Compounds of Formula I, wherein D is N, T is CH, M is C, Q is N, q is 0and R³ is COCH₂CH₂ linked together with the nitrogen at Q, can beprepared according to the synthetic sequence shown in Scheme 9 andfurther detailed in the Examples section following.2,6-Dichloro-3-nitropyridine (1) was aminated to give (2) and coupledwith 4-acetylaminophenol to give ether (3). After hydrogenation, andsubsequent cyclization with BrCN to give (4), compound (4) was cyclizedby ester hydrolysis through heating to provide (5). Using methodssimilar to those shown in the previous Schemes, hydrolysis to give (6)and coupling with isocyanate yielded urea (7).

Compounds of Formula I, wherein D is CH, T is CH, M is N, Q is CH, and qis 0, can be prepared according to the synthetic sequence shown inScheme 10 and further detailed in the Examples section following. Ether(2), derived from 5-bromo-2-nitroaniline (1), was cyclized withClCH₂CONHCO₂Me to give pyridoimidazole (3). Using methods similar tothose shown in the previous Schemes, hydrolysis to give (4) and couplingwith isocyanate yielded urea (5).

Compounds of Formula I, wherein D is CH, T is N, M is C, Q is N(R⁷)_(p),R⁷ is H, either p or q is 1, and the other is 0, can be preparedaccording to the synthetic sequence shown in Scheme 11 and furtherdetailed in the Examples section following. A nitro moiety was added toethyl N-(5-bromopyridine-3-yl)carbamate (1) to give (2), followed byhydrolysis to give (3). Using methods similar to those shown in theprevious Schemes, coupling with phenol derivative gave (4),hydrogenation and cyclization in the presence of acid gave (5),hydrolysis gave (6), and coupling with isocyanate yieldedpyridoimidazole (7).

Compounds of Formula I, wherein X is CO, CH₂, CH(OH), D is CH, T is CH,M is C, Q is N(R⁷)_(p), R⁷ is H, either p or q is 1, and the other is 0,can be prepared according to the synthetic sequence shown in Scheme 12and further detailed in the Examples section following. Friedel-Craftscondensation with the halide of (1) and acetoanilide was carried out togive ketone (2). Using methods similar to those shown in the previousSchemes, reduction with zinc and cyclization gave (3), hydrolysis, andcoupling with isocyanate yielded pyridoimidazole (4). Also, reductionwith NaBH₄ gave carbinol (5), followed by further reduction with Et₃SiHprovided benzyl derivative (6).

According to Scheme 13, amino-(4-methoxyphenyl)-methylpolystyrene resinwas first loaded with 4-chloro-2-fluoronitrobenzene in the presence ofDIEA. The chlorine of compound (1) was displaced with the oxygen of the4-aminophenol using NaH as the base to arrive at (2). The free aminogroup of (2) was then activated with p-nitrophenyl chloroformate, theexcess of which was washed away before the amines were added. For thisstep, the resin was split into 21 equal batches and twenty (20)five-membered heteroaryl amines and one substituted aniline were used toafford (3). The nitro group of (3) was reduced with tin chloride to givediamine (4). Cyclization with Fmoc-NCS resulted in the Fmoc-protectedaminobenzimidazole (5). Each resin batch was split again into four evenportions. They were deprotected and acylated with four differentcarboxylic acids. Finally, the resin was treated with 23:2:75 (v/v/v)TFA/H₂O/DCM to yield 84 discrete benzimidazoles (7).

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); psi (pounds per square inch); M (molar); mM (millimolar);i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); rt (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); T_(r) (retentiontime); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); AcOEt(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA(meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOC(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm(atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); BSA (bovine serum albumin) ATP (adenosinetriphosphate); HRP (horseradish peroxidase); DMEM (Dulbecco's modifiedEagle medium); HPLC (high pressure liquid chromatography); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); HBTU(O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate).HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); DPPA(diphenylphosphoryl azide); EtOH (Ethanol) fHNO₃ (fumed HNO₃); DIC(1,3-Diisopropylcarbodiimide); EDC(1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride; DIEA(N,N-Diisopropylethylamine); and EDTA (ethylenediaminetetraacetic acid).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, a Brucker AVANCE-400, or a General ElectricQE-300. Chemical shifts are expressed in parts per million (ppm, δunits). Coupling constants are in units of hertz (Hz). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APliii spectrometer; LC-MS were recorded on amicromass 2MD and Waters 2690; high resolution MS were obtained using aJOEL SX-102A spectrometer. All mass spectra were taken underelectrospray ionization (ESI), chemical ionization (CI), electron impact(EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectrawere obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaClcell. Most of the reactions were monitored by thin-layer chromatographyon 0.25 mm E. Merck silica gel plates (60F-254), visualized with UVlight, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution.Flash column chromatography was performed on silica gel (230–400 mesh,Merck).

A further note on characterization, when R⁷ is H in a compound ofFormula (I) wherein Q is N(R⁷)_(p), it is not identifiable whether p orq is 1 due to the tautomerism.

Preparation of Intermediates Intermediate 15-(4-Acetamidophenoxy)-2-nitroaniline

To a solution of 4-acetamidophenol (7.56 g, 50 mmol) in DMF (20 ml) wasadded 60% NaH (2.2 g) followed by 5-chloro-2-nitroaniline (9.06 g, 50mmol). The mixture was heated to 120° C. overnight. After cooling, 800ml of water was added and the resultant solid was collected byfiltration. Desiccation in vacuo gave intermediate 1 as a brown solid(13.75 g, 96%): MS m/e 286 (M−1).

Intermediate 1A 5-(3-Acetamidophenoxy)-2-nitroaniline

3-Acetamidophenol was utilized instead of 4-acetamidophenol, accordingto the same procedure for Intermediate 1 to prepare Intermediate 1A: MSm/e 286 (M−1).

Intermediate 2 4-(4-Acetamidophenoxy)phenylene-1,2-diamine

Na₂S₂O₄ (28.2 g, 160 mmol) was added to a solution of5-(4-Acetamidophenoxy)-2-nitroaniline (Intermediate 1) (13.7 g, 48 mmol)in EtOH (600 ml) and H₂O (150 ml). The yellow mixture was refluxed withvigorous stirring until the color disappeared. After cooling, themixture was washed with brine and the product was extracted with AcOEt.The AcOEt layer was dried over MgSO₄, filtered and evaporated to giveintermediate 2 as a brown film (10.2 g, 83%): MS m/e 258 (M+1).

Intermediate 2A 4-(3-Acetamidophenoxy)phenylene-1,2-diamine

Intermediate 1A was treated instead of Intermediate 1 to giveIntermediate 2A: MS m/e 258 (M+1).

Intermediate 3 Methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate

Method A

A mixture of 4-(4-Acetamidophenoxy)phenylene-1,2-diamine (Intermediate2) (750 mg, 2.9 mmol) and1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (600 mg) in EtOH (13ml) was refluxed overnight. After cooling to rt, diethyl ether was addedto form a solid (830 mg), which was collected by filtration. 1N—HCl (150ml) was poured to this acetylated version of intermediate 3 (7.7 g, 23mmol). The mixture was heated to reflux (105° C.) for 2 h. Aftercooling, aq. NH₃ (30%, 20 ml) was added. The precipitate thus formed wascollected by filtration with suction and dried in vacuo. The solidmaterial was then suspended in MeOH (150 ml) and heated to 70° C. for 30min. with stirring to dissolve a minor by-product. After cooling, theundissolved material was collected by filtration and dried in vacuo togive intermediate 3 as a brown solid (6.75 g, 99%): MS m/e 299 (M+1).

Method B

A mixture of 3,4,4′-triaminodiphenylether (12.6 g, 59 mmol) and1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (26.7 g) was refluxedovernight. After cooling, Et₂O was added to form a precipitate, whichwas then collected by filtration. The solid thus obtained (4 g) wasdissolved in MeOH (20 ml) and treated with 2N—HCl (20 ml) and then withconc.HCl (3 ml). Stirring was continued overnight at rt. The mixture wasevaporated to remove MeOH. The resultant material was neutralized withaq. NaOH to give intermediate 3 as an off-white solid: MS m/z 299 (M+1).

Intermediate 3A Methyl(5-(3-aminophenoxy)-1H-benzimidazol-2-yl)carbamate

Intermediate 3A was prepared following the Method A procedure for thepreparation of Intermediate 3 using Intermediate 2A instead ofIntermediate 2: MS m/z 299 (M+1).

Intermediate 3B Methyl(5-(4-aminophenylthio)-1H-benzimidazol-2-yl)carbamate

Intermediate 3B was prepared following the Method A procedure for thepreparation of Intermediate 3 starting from 4-acetamidophenylthiol: MSm/z 315 (M+1).

Intermediate 3CBenzyl(5-(4-(N,N′-bis(benzyloxycarbonyl)amidino)aminophenoxy)-1H-benzimidazol-2-yl)carbamate

A mixture of 3,4,4′-triaminodiphenyl ether (5.0 g, 23.2 mmol) and1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (16.5 g, 46.0 mmol)in dry MeOH (100 ml) was refluxed overnight. The reaction mixture wascooled to room temperature and ether was added. An off white solid wasgenerated and collected by filtration and washed with ether and dried invacuo. 14.3 g of Intermediate 3C was obtained as off white powder. Yield89.9% ¹H NMR (DMSO-d₆) δ 11.82 (br,1H), 11.40 (br,1H), 7.51–7.27 (m,20H), 7.03 (s, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 5.24 (s, 4H), 5.02 (s,2H); MS m/e 685 (M+1).

Intermediate 3D Benzyl(5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate

14.3 g of Intermediate 3C was dissolved in 300 ml of MeOH and 300 ml of2M HCl and stirred for 3 days at 50° C. Then MeOH was removed byevaporation and 2M of NaOH solution was added to pH 9.0. The generatedsolid was collected by filtration and washed with water and dried invacuo. Yield 78.0% (7.61 g) ¹H NMR (DMSO-d₆) δ 7.48–7.33 (m, 8H),7.01–6.94 (m, 3H), 6.89 (d, 2H), 6.78 (dd, 1H), 5.24 (s, 2H); MS m/e 375(M+1).

Intermediate 4 5-(4-Aminophenoxy)-2-nitroaniline

To a solution of 4-aminophenol (5.0 g, 46 mmol) in DMF (120 ml) wasslowly added 60% NaH (2.0 g, 50 mmol), followed by5-chloro-2-nitroaniline (8.7 g). The mixture was heated to 90° C. andstirred overnight. The reaction mixture was poured onto aq. NH₄Cl toform a solid, which was collected by filtration, washed with hexane anddried to give intermediate 4 as a yellow solid (12.0 g, >99%): MS m/e244 (M−1).

Intermediate 55-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylaminophenoxy)-2-nitroaniline

A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate (10.0 g, 48.8mmol) and 5-(4-Aminophenoxy)-2-nitroaniline (Intermediate 4)(11.6 g,47.3 mmol) in dry THF (200 ml) was stirred overnight at rt. Aftertreatment with activated carbon, the solvent was evaporated.Purification of the crude material by column chromatography(hexane-AcOEt, 1:2) afforded intermediate 5 as a yellow solid (21.6g, >98%): MS m/e 449 (M−1).

Intermediate 64-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phenylene-1,2-diamine

Pd/C (5%, 3.0 g) was introduced to a solution of5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline(Intermediate 5) (21.6 g, 48 mmol) in ethanol (200 ml) under Ar. Thestarting material was hydrogenated under a H₂ atmosphere for 3 dayswhile being stirred. The reaction mixture was then filtered throughcelite and evaporated to give intermediate 6 as a black film. This crudematerial was chromatographed through silica gel (hexane-AcOEt,4:1–3:1–2:1–1:1–0:1) to give purified intermediate 6 (13.0 g, 64%): MSm/e 421 (M+1).

Intermediate 7N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide

To a mixture of 5-hydroxy-2-acetylaminobenzimidazole (382 mg, 2 mmol)and Cs₂CO₃ (978 mg, 3 mmol) in DMF (20 ml) was added5-bromo-2-nitropyridine (550 mg, 2 mmol) at room temperature. After 2hours of stirring, the mixture was poured into water and extracted withAcOEt. The organic solvent was washed with water and brine, thenevaporated to obtain a crude product. It was purified with silica gelcolumn chromatography (CHCl₃—MeOH). The pure fractions were collected toprovide intermediate 7, which was then used for the subsequent reduction(314 mg, 50%).

Intermediate 8N-(5-(2-Amino-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide

N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide (Intermediate7) was hydrogenated under an H₂ atmosphere with Pd—C (10%) in MeOH.After the reaction was complete, the solid was filtered off, and thefiltrate was evaporated to give intermediate 8 (47 mg, 17%): ¹H NMR(DMSO-d₆) δ 11.56 (brs, 1H) 7.51 (d, 1H), 7.32 (d, 1H), 7.05 (dd, 1H),6.97 (d, 1H), 6.74 (dd, 1H), 6.70 (d, 1H), 5.02 (br s, 2H), 3.74 (s,3H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 284(M+1).

Intermediate 8A 4-(4-Nitrophenoxy)-2-nitroaniline

To a solution of 4-hydroxy-2-nitroaniline (3.08 g, 20.0 mmol) in DMF (30mL) was added NaH (60% oily, 880 mg, 22.0 mmol) followed by1-fluoro-4-nitrobenzene (2.33 mL, 22.0 mmol). The mixture was stirred at90° C. overnight. After cooling, the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave the title compound (4.56 g, 83%): MS m/e 274 (M−1).

Intermediate 8B N-Methyl-4-(4-nitrophenoxy)-2-nitroaniline

To a mixture of NaH (60% oily, 320 mg, 8.0 mmol) in DMF (30 mL) wasadded a solution of 4-(4-nitrophenoxy)-2-nitroaniline (Intermediate8A-2.00 g, 7.3 mmol) in DMF (30 mL) at 0° C. followed by an excessamount of Mel (2.0 mL). The mixture was stirred at 0° C. for 1.5 hrsthen at room temperature overnight. The mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂columnchromatography gave the title compound (2.10 g, quant). ): ¹H NMR(CDCl₃-d₁) δ 3.08 (d, 3H), 6.94 (d, 1H), 7.00 (d, 2H), 7.30 (dd, 1H),7.97 (d, 1H), 8.08 (brs, 1H), 8.22 (d, 2H).

Intermediate 8C Methyl(1-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate

To a mixture of N-methyl-4-(4-nitrophenoxy)-2-nitroaniline (Intermediate8B -2.10 g, 2.27 mmol) in MeOH (100 mL) was added 5% Pd—C (catalyticamount) and stirred at room temperature under H₂ atmosphere. After 7hrs, the catalyst was removed by filtration then the solvent wasevaporated off. The residual mixture was dissolved into MeOH (50 mL) andadded 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.0 g, 14.5mmol). The mixture was refluxed overnight. The solvent was removed byevaporation and sequence purification on SiO₂ column chromatography gavetitle compound (87.3 mg, 4%): MS m/e 313 (M+1).

Intermediate 8D N-methyl-5-chloro-2-nitroaniline

To a solution of 5-chloro-2-nitroaniline (1.73 g, 10.0 mmol) in DMF (40mL) was added NaH (60% oily, 880 mg, 22.0 mmol) at 0° C. followed byexcess amount of Mel (3.0 mL). The mixture was stirred at 0° C. for 1 hrthen at room temperature overnight. The mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave the title compound (1.86 g, quant): ¹H NMR (DMSO-d₆)δ 2.95 (d, 3H), 6.69 (dd, 1H), 7.03 (d, 1H), 8.08 (d, 1H), 8.28 (br,1H).

Intermediate 8E N-(2-(dimethylamino)ethyl)-5-chloro-2-nitroaniline

To a solution of 3-fluoro-4-nitro-1-chlorobenzene (1.75 g, 10.0 mmol) inDMSO (50 mL) was added K₂CO₃ (2.76 g, 20.0 mmol) followed byN,N-dimethylaminoethylamine (1.21 mL, 11.0 mmol) at 0° C. The mixturewas stirred at 0° C. for 5 min. before being stirred at room temperatureovernight. The mixture was poured into water then extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave the title compound (2.29 g, 94%): MS m/e 244, 246(M+1).

Intermediate 8F N-(2-(4-morpholino)ethyl)-5-chloro-2-nitroaniline

The title compound was prepared following the procedure for Intermediate8E using 2-(4-morpholino)ethylamine: MS m/e 286, 288 (M+1).

Intermediate 8G 4-(3-Methylamino-4-nitrophenoxy)aniline

To a mixture of NaH (60% oily, 440 mg, 11.0 mmol) in DMF (30 mL) wasadded a solution of 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL)followed by N-methyl-5-chloro-2-nitroaniline (Intermediate 8D-2.02 g,10.0 mmol) in DMF (20 mL). The mixture was stirred at 90° C. overnight.After cooling, the mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over Na₂SO₄ thenevaporated. Sequence purification on SiO₂ column chromatography gave thetitle compound (2.44 g, 94%): MS m/e 260 (M+1).

Intermediate 8H4-(3-(2-(Dimethylamino)ethylamino)-4-nitrophenoxy)aniline

Intermediate 8H is prepared using a procedure similar to Intermediate8H. MS m/e 317 (M+1).

Intermediate 8I 4-(3-(2-(4-Morpholino)ethylamino)-4-nitrophenoxy)aniline

The title compound was prepared following the procedure for Intermediate8H using Intermediate 8F. MS m/e 359 (M+1).

Intermediate 8J Methyl(3-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate

After hydrogenation of 4-(3-methylamino-4-nitrophenoxy)aniline(Intermediate 8G-519.2 mg, 2.0 mmol) with 5% Pd—C in MeOH (20 mL),1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0 mmol)and AcOH (2.0 mL) was added then stirred at 85° C. for 5.5 hrs. Aftercooling, the mixture was added 2N HClaq. (25 mL) then stirred at 65° C.for 2 hrs. The mixture was passed through celite pad to remove catalystand the solvent was removed by evaporation. The residue was extractedwith ethyl acetate. The organic layer was washed with NH₄OH(aq). andbrine, dried over Na₂SO₄ then evaporated. Sequence purification on SiO₂column chromatography gave the title compound (529.1 mg, 85%): MS m/e313 (M+1).

Intermediate 8K Methyl(3-(2-(N,N-dimethylamino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate

The title compound was prepared following the procedure for Intermediate8J using Intermediate 8H. MS m/e 370 (M+1).

Intermediate 8L Methyl(3-(2-(4-morpholino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate

The title compound was prepared following the procedure for Intermediate8J using Intermediate 8I. MS m/e 412 (M+1).

Intermediate 9 Ethyl N-(5-bromopyridine-3-yl)carbamate

To a solution of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in ethanol(300 mL) was added DPPA (21.6 mL, 100.0 mmol) followed by triethylamine(14.3 mL, 103.0 mmol) then refluxed overnight. After cooling, a halfamount of solvent was removed by evaporation. The ethanol solution wasextracted with ethyl acetate. The organic layer was washed with NaHCO₃(aq) and brine, dried over Na₂SO₄ then evaporated. Sequence purificationon SiO₂ column chromatography gave the title compound (4.55 g, 19%): MSm/e 245, 246 (M+1).

Intermediate 9A 5-Bromo-2-nitropyridine-3-ylamine

To a mixture of concentrated H₂SO₄ (3.0 mL) and fHNO₃ (2.1 mL),3-bromo-5-(ethoxycarbonyl)aminopyridine (Intermediate 9–20.0 g, 99.0mmol) was portionwise added at 0° C. After stirring at 0° C. for 5 min.,the mixture was stirred at room temperature overnight. The mixture waspoured into ice-water then basified with aqueous NH₄OH. The mixture wasextracted with ethyl acetate. The organic layer was washed with aqueousNH₄OH and brine, dried over Na₂SO₄ then evaporated. Sequencepurification on SiO₂ column chromatography gave5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 54%).

To a solution of 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57g, 5.4 mmol) in ethanol (2.5 mL) was added KOH (813 mg, 14.5 mmol) inwater (12.5 mL) and stirred at 90° C. for 1 hr then at room temperaturefor 1 hr. The mixture was added water. The formed precipitate wascollected by filtration, washed with water then dried under reducedpressure to give the title compound (1.08 g, 92%): MS m/e 216, 218(M−1).

Intermediate 9B 3-Nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine

To a solution of 2-amino-6-chloro-3-nitropyridine (2.77 g, 16.0 mmol) inDMF (55 mL) was added 4-acetylaminophenol (2.67 g, 17.5 mmol) followedby K₂CO₃ (3.3 g, 5.0 mmol) and stirred at room temperature for 2 hrs.The solvent was removed by evaporation. To the residue, water was addedto form a precipitate. The solid was collected by filtration, washedwith water and ethyl acetate then dried under reduced pressure to givethe title compound (4.32 g, 94%): MS m/e 289 (M+1).

Intermediate 9C2-Nitro-5-(4-(tert-butoxycarbonylamino)phenoxy)pyridine-3-ylamine

To a solution of 5-bromo-2-nitropyridine-3-ylamine (436 mg, 2.0 mmol) inDMF (10 mL) was added Cs₂CO₃ (977 mg, 3.0 mmol) followed by4-(t-butoxycarbonyl)aminophenol (459 mg, 2.2 mmol) in DMF (10 mL) at 0°C. then stirred at room temperature for 3 days. The mixture wasextracted with ethyl acetate. The organic layer was washed with NaHCO₃(aq) and brine, dried over Na₂SO₄ then evaporated. Sequence purificationon SiO₂ column chromatography gave the title compound (624.2 mg, 90%):MS m/e 347 (M+1).

Intermediate 9D Methyl(5-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate

After hydrogenation of 3-nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine(2.02 g, 7.0 mmol) with 5% Pd—C in MeOH (70 mL), catalyst was removed byfiltration.

To the MeOH solution, 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea(1.73 g, 8.4 mmol) was added and stirred at 75° C. After 8 days, AcOH(15 mL) was added and stirred at 80° C. overnight. Additional1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4 mmol)was added then stirred at 80° C. overnight. After cooling, the mixturewas poured into NaHCO₃ (aq). Formed precipitate was collected byfiltration, washed with ethyl acetate then dried under reduced pressureto give methyl (5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate(983.0 mg, 41%). To a solution of methyl(5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (102.4 mg, 0.3mmol) in water (3 mL) was added 2N HCl (aq) (3.0 mL) then refluxed for 1hr and stirred at room temperature for 1 hr. The mixture was extractedwith ethyl acetate. The organic layer was washed with NH₄OH (aq), driedover Na₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave the title compound (33.6 mg, 37%): MS m/e 342 (M+1).

Intermediate 9E Methyl(6-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate

The same procedure described in Intermediate 9D gave methyl(5-(4-(tertbutoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate.To a solution of methyl(5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate(160.8 mg, 0.4 mmol) in methanol (10 mL) was added 2N HCl (aq) (10 mL)then stirred at room temperature overnight. The solution was removed byevaporation then the residue was extracted with ethyl acetate. Theorganic layer was washed with NaHCO₃ (aq) and brine, dried over Na₂SO₄then evaporated. The residual solid was washed with ethyl acetate thendried under reduced pressure to give the title compound (95.3 mg, 80%):MS m/e 300 (M+1).

Intermediate 9F Ethyl 3-(6-Chrolo-3-nitropyridine-2-ylamino)propanoate

To a solution of 2,6-dichloro-3-nitropyridine (4.83 g, 25.0 mmol) inacetonitrile (100 mL) was added β-alanine hydrochloride (4.61 g, 30.0mmol) followed by K₂CO₃ (10.4 g, 75.0 mmol). After stirring at roomtemperature for 3 days, the solvent was removed by evaporation. Theresidue was extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over Na₂SO₄ then evaporated. Sequencepurification on SiO₂ column chromatography gave the title compound (5.01g, 73%): MS m/e 272, 274 (M−1).

Intermediate 9G Ethyl3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate

To a solution of ethyl 3-(6-chrolo-3-nitropyridine-2-ylamino)propanoate(Intermediate 9F-2.72 g, 9.94 mmol) in DMF (30 mL) was added4-acethylaminophenol (1.66 g, 11.0 mmol) followed by K₂CO₃ (2.1 g, 14.9mmol) then stirred at room temperature for 1 hr. To the mixture, waterwas added to form precipitate. The solid was collected by filtration,washed with water and ethyl acetate then dried under reduced pressure togive the title compound (3.79 g, 98%): MS m/e 389 (M+1).

Intermediate 9H2-Amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindolidine

After hydrogenation of ethyl3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate(Intermediate 9G-1.94 g, 5.0 mmol) with 50% Pd—C in MeOH (25 mL) andevaporation, the residue was added ethanol (65 mL) and BrCN (1.84 g, 17mmol) and stirred at room temperature overnight. The mixture wasextracted with ethyl acetate. The organic layer was washed with NaHCO₃(aq) and brine, dried over Na₂SO₄ then evaporated. The residue waswashed with ethyl acetate then MeOH then dried under reduced pressure togive the title compound (800.0 mg, 42%): MS m/e 384 (M+1).

Intermediate 9I3,4-Dihydro-6-(4-aminophenoxy)-1,4a,5-triazacarbazol-2-one

To a solution of2-amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindolidine(Intermediate 9H-200.0 mg, 0.52 mmol) in ethanol (10 mL) was addedconc.HCl (1.0 mL) and stirred at 85° C. overnight. After evaporation toremove ethanol, DMF (10 mL) was added to the mixture then heated to 120°C. for 2 hrs. After cooling, the solvent was removed by evaporation thenthe residue was washed with MeOH. The result solid was added 2M HCl (12mL) and stirred at room temperature overnight. The mixture was basifiedwith NH₄OH (aq). The formed precipitate was collected, washed with waterthen dried under reduced pressure to give the title compound (103.4 mg,67%): MS m/e 296 (M+1).

Intermediate 9J 5-(4-Acetamidophenoxy)pyridine-2-ylamine

To a solution of 5-bromo2-nitropyridine (2.03 g, 10.0 mmol) in DMF (30mL) was added Cs₂CO₃ (4.9 g, 15.0 mmol) followed by 4-acetylaminophenol(1.66 g, 11.0 mmol) in DMF (30 mL) at 0° C. then stirred at roomtemperature overnight. The mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over. Na₂SO₄ thenevaporated. Sequence purification on SiO₂ column chromatography andrecrystalization from ethyl acetate gave5-(4-acetamidophenoxy)-2-nitropyridine (1.62 g, 59%). Hydrogenation of5-(4-acetamidophenoxy)-2-nitropyridine (879.0 mg, 3.22 mmol) with 5%Pd—C in MeOH (80 mL) gave the title compound (575.7 mg, 74%): MS m/e 244(M+1).

Intermediate 9K Methyl (5-(4-aminophenoxy)azaindolizine-2-yl)carbamate

To a solution of 5-(4-acetamidophenoxy)pyridine-2-ylamine (Intermediate9J170.2 mg, 0.7 mmol) in DMF (2 mL) was addedN-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol). The mixturewas stirred at 80° C. overnight. AdditionalN-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol) was added andstirred at 80° C. overnight. After cooling, the mixture was extractedwith ethyl acetate. The organic layer was washed with NaHCO₃ (aq) andbrine, dried over Na₂SO₄ then evaporated. Sequence purification on SiO₂column chromatography gave methyl(5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (51.7 mg, 22%). Toa solution of methyl(5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (34.0 mg, 0.1 mmol)in water (2 mL) was added 2N HCl (aq) (2.0 mL) then refluxed for 1 hrand stirred at room temperature for 1 hr. The mixture was added NH₄OH(aq). Formed precipitate was collected by filtration, washed with waterthen dried under reduced pressure to give the title compound (22.0 mg,74%): MS m/e 299 (M+1).

Intermediate 10 4-(4-Nitrophenoxy)aniline

To a mixture of NaH (60% oily, 880 mg, 22.0 mmol) in DMF (40 mL) wasadded a solution of 4-aminophenol (2.40 g, 22.0 mmol) in DMF (30 mL)followed by 1-fluoro-4-nitrobenzene (2.12 mL, 20.0 mmol). The mixturewas stirred at 90° C. overnight. After cooling, the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄ then evaporated. Sequence purification onSiO₂ column chromatography gave the title compound (4.60 g, quant): MSm/e 229 (M−1).

Intermediate 10A 6-(4-Nitrophenoxy)benzthiazole-2-ylamine

See the procedure following for Intermediate 10B.

Intermediate 10B 4-Bromo-6-(4-nitrophenoxy)benzthiazole-2-ylamine

To a solution of 4-(4-nitrophenoxy)aniline (Intermediate 10–1.15 g, 5.0mmol) in AcOH (5 mL) was added KSCN (729 mg, 7.5 mmol). The mixture wascooled to 0° C. and added a solution of Br₂ (256 μL, 5.0 mmol) in AcOH(6 mL) then stirred at room temperature overnight. The mixture waspoured into H₂O, basified with NH₄OH (aq), then extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave Intermediate 10A (941.5 mg, 66%): MS m/e 288 (M+1)and Intermediate 10B (223.7 mg, 12%): MS m/e 366, 368 (M+1).

Intermediate 10CN-(6-(4-Nitrophenoxy)benzthiazole-2-yl)methanesulfonamide

To a solution of Intermediate 10A (1.15 g, 4.0 mmol) in pyridine (10 ml)was added mesyl chloride (1.55 ml, 20 mmol) at 0° C. and stirred overnight at 0° C.—room temperature. Then potassium carbonate (5.5 g, 40mmol) in water (20 ml) and MeOH (20 ml) was added and stirred 4 days at60° C. MeOH was removed by evaporated and desired compound was extractedwith AcOEt ×3 and organic layer was washed with water and brine anddried over with MgSO₄. And purified by column chromatography (AcOEt-DCM,1:1,3:1) and crystallized from AcOEt-Hexane. 300 mg of Intermediate 10Cwas obtained as yellow solid. Yield 20.5% MS m/e 366 (M+1).

Intermediate 10DN-(6-(4-Aminophenoxy)benzthiazole-2-yl)methanesulfonamide

To a solution of Intermediate 10C (100 mg, 0.27 mmol) in acetic acid (1ml) was added Zn (54 mg, 0.81 mmol) and stirred over night at roomtemperature. Acetic acid was removed by evaporation and residue wasdissolved in DMF and filtrated. Filtrate was purified by SPE(SCX) tube(washed with MeOH/DMF and eluted with NH₃/MeOH). NH₃/MeOH eluent wascollected and 72 mg of Intermediate 10D was obtained. Yield 79.5% MS m/e336 (M+1).

Intermediate 10E Methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate

To a mixture of 5-(4-nitrophenoxy)benz-3-thiazole-2-ylamine (430.5 mg,1.5 mmol) in pyridine (6 mL) and DMF (9 mL) was dropwise added an excessamount of ClCO₂Me (ca 0.8 mL) at room temperature. The mixture was addedwater. The formed precipitate was collected by filtration, washed withwater and MeOH and dried under reduced pressure to give the titlecompound (503.7 mg, 97%): MS m/e 346 (M+1).

Intermediate 10F Methyl(4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate

The title compound was prepared following the procedure for Intermediate10E using Intermediate 10A. MS m/e 424, 426 (M+1)

Intermediate 10G Methyl (6-(4-aminophenoxy)benzthiazole-2-yl)carbamate

To a solution of methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate(Intermediate 10E-172.7 mg, 0.5 mmol) in DMF (5 mL) was added SnCl₂(474.0 mg, 2.5 mmol) and stirred at room temperature for 4 days. Themixture was extracted with ethyl acetate, and the organic layer waswashed with NaHCO₃aq. and dried over Na₂SO₄ then evaporated to removesolvent. The residue dissolved in small amount of DMF was charged on SCXcolumn chromatography then washed with MeOH then eluted with NH₃—MeOH togive the title compound (69.2 mg, 44%): MS m/e 316 (M+1).

Intermediate 10H Methyl(4-bromo-6-(4-aminophenoxy)benzthiazole-2-yl)carbamate

To a solution of methyl(4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate (Intermediate10F-65.3 mg, 0.15 mmol) in AcOH (2 mL) was added Zn powder (300 mg) andstirred at room temperature for 2 hrs. The insoluble materials wereremoved by filtration. The solvent was removed by evaporation. Theresidue was charged on SCX column chromatography then washed with MeOHthen eluted with NH₃—MeOH to give the title compound (39.6 mg, 65%): MSm/e 394, 396 (M+1).

Intermediate 11 4-(3-Benzyloxy-4-nitrophenoxy)aniline

To a solution of 5-fluoro-2-notrophenol (9.43 g, 60.0 mmol) in acetone(100 mL) was added K₂CO₃ (12.4 g, 90.0 mmol) followed by benzylbromide(8.6 mL, 72.0 mmol) and acetone (60 mL) then stirred at room temperatureovernight. The mixture was extracted with ethyl acetate, and the organiclayer was washed with water and brine, dried over Na₂SO₄ thenevaporated. Sequence purification on SiO₂ column chromatography gave2-benzyloxy-4-nitro-1-fluorobenzene (11.97 g, 81%).

To a mixture of NaH (60% oily, 440.0 mg, 11.0 mmol) in DMF (20 mL) wasdropwise added 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL) followedby 2-benzyloxy-4-nitro-1-fluorobenzene (2.47 g, 10.0 mmol) in DMF (15mL). The mixture was stirred at room temperature for 10 min then at 80°0C. overnight. After cooling, the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄ then evaporated. Sequence purification on SiO₂ columnchromatography gave the title compound (3.30 g, 98%): MS m/e 337 (M+1).

Intermediate 11AN-(4-(3-Benzyloxy-4-nitrophenoxy)phenyl)(2-fluoro-5-(trifluoromethyl)phenylamino)formamide

To a mixture of 4-(3-benzyloxy-4-nitrophenoxy)aniline (Intermediate11–1.34 g, 4.0 mmol) in THF (40 mL) was added5-fluoro-3-trifruolomethylphenyl isocyanate (636 μL, 4.4 mmol) andstirred at room temperature overnight. The mixture was added MeOH thenthe solvent was removed by evaporation. The residue was purified on SiO₂column chromatography gave the title compound (2.17 g, quant): MS m/e542 (M+1).

Intermediate 11B6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyloxy)benzoxazol-2-ylamine

After hydrogenation ofN-(4-(3-benzyloxy-4-nitrophenoxy)phenyl)(2-fluoro-5-(trifluoromethyl)phenylamino)formamide(Intermediate 11A-542 mg, 1.0 mmol) with 5% Pd—C in MeOH (10 mL), BrCN(800 mg, 7.6 mmol) was added and stirred at room temperature for 4 days.The mixture was added NaHCO₃ (aq) and stirred for 1 day. The mixture wasextracted with ethyl acetate. The organic layer was washed with NaHCO₃(aq) and brine, dried over Na₂SO₄ then evaporated. Sequence purificationon SiO₂ column chromatography gave the title compound (237 mg, 53%): MSm/e 447 (M+1).

Intermediate 11C 4-(4-(Acetamido)phenylcarbonyl)-1,2-dinitrobenzene

A mixture of 3,4-dinitrobenzoyl chloride (4 mmol), acetoanilide (540 mg,4 mmol), and AlCl₃ (1.6 g) in CH₂Cl₂ was heated at 40° C. for 24 h. Theslurry was washed with HCl (aq) and the product was extracted withether. It was washed with K₂CO₃ (aq), dried, and evaporated.Purification by column-chromatography on silica-gel (hexane:AcOEt=1:3)provided 87 mg of the title compound; MS m/e 328 (M−1).

Intermediate 11D 4-(4-Aminophenylcarbonyl)-1,2-dinitrobenzene

Using the methods of Intermediate 2 and then Intermediate 3 (Method A),Intermediate 11D was prepared from Intermediate 11C; MS m/e 311 (M+1).

Intermediate 12 4-Nitro-3-fluorophenyl tetrahydropyranyl ether

To the mixture of 3-fluoro-4-nitrophenol (25 g, 0.160 mol) and3,4-dihydro-2H-pyran (14 g, 0.167 mol)in dicloromethane (200 ml),pyridinium p-toluenesulfonate (4.0 g, 16 mol) was added portionly underice-water bath. After overnight at room temperature, the reactionmixture was pored to Si-column chromatography. Eluting by Hexane Ethylacetate (3:1), the desired product was obtained at 35.5 g (92%) as lightyellow solid.

Intermediate 12A 3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether

To the solution of Intermediate 12 (20 g, 0.083 mol) in DMSO (150 ml),benzylamine (8.9 g, 0.083 mol) and K₂CO₃ (23 g) were added at roomtemperature. NH₂-TLC by eluted Hexane-AcOEt showed reaction complete.Water was added to the mixture, then, extracted by AcOEt at twice. Allorganic layer was evaporated. The residue is used to the next reduction.MS m/e 329 (M+1).

Intermediate 12B 3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether

The product of Intermediate 12A was reduced in a usual manner to give2-benzylaminoaniline derivative (see Intermediate 2). To the suspensionof crude diamino phenylene (26.3 g, 88 mmol) derivatives in methanol(300 ml), bromocyanide (9.35 g, 1 equiv.) was added at 0° C. After 15min, the ice-bath was removed and stirred for 1 hr at room temperature.After evaporation of the methanol solution, saturated NaHCO₃ (300 ml)and AcOEt (100 ml) were added to the residue. Generated precipitateswere filtered and washed with water to give a crude powder (21.68 g). MSm/e 324 (M+1).

Intermediate 12C N-(1-Benzyl-6-hydroxy-1H-benzimidazol-2-yl)acetamide

To the suspension of Intermediate 12B (2 g, 6.1 mmol) in THF (5 ml),acetic anhydride (2.3 ml) was added at room temperature. After 3 hr atroom temperature, THF was evaporated. Ice-water was added to theresidue, then conc. HCl and methanol were added carefully at 0 C. After30 min' stirring, the acidic solution was neutralized by NaOH andNaHCO₃. The generated precipitate was collected, washed with Et₂O, anddried to give the title compound. MS m/e 282 (M+1).

Intermediate 12D1-Benzyl-6-hydroxy-2-(tert-butoxycarbonylamino)-1H-benzimidazole

1-Benzyl-6-hydroxy-2-amino-1H-benzimidazole was treated with BOC₂O inpyridine, followed by hydrolysis with NaOH (aq) to give the titlecompound; MS m/e 340 (M+1).

Intermediate 12E Tert-ButylN-(1-benzyl-6-(6-aminopyridin-3-yloxy)-1H-benzimidazol-2-yl)

Coupling of Intermediate 12D with 3-bromo-6-nitropyridine and subsequenthydrogenation over Pd/C gave the title compound; MS m/e 432 (M+1).

Intermediate 13A 1-(6-(4-Nitrophenoxy)benzthiazol-2-yl)-3-butylurea

Intermediate 13A was prepared following a similar procedure for Example1 using Intermediate 10A. MS m/e 387 (M+1)

Intermediate 13B 1-(6-(4-Aminophenoxy)benzthiazol-2-yl)-3-butylurea

Intermediate 13B was prepared following a similar procedure forIntermediate 10D using Intermediate 13A. MS m/e 357 (M+1)

Intermediate 14A Resin-Bound 5-Chloro-2-nitroaniline

Amino-(4-methoxyphenyl)-methylpolystyrene (loading 1.69 mmol/g, 7.00 g,11.8 mmol) was soaked in DMSO in a peptide vessel for 30 min. Thesolvent was then drained. DIEA (11.3 mL, 65.1 mmol) in DMSO (88 mL) wasadded to the resin, followed by 4-chloro-2-fluoronitrobenzene (10.4 g,59.2 mmol). The mixture was shaken at room temperature for 19 h, atwhich point it was drained. The resin was washed with DMSO (3×), EtOH(3×), DMF (3×), MeOH (3×) and DCM (3×). It was then dried under vacuumovernight. A small sample (approx. 10 mg) was treated with 23:2:75(v/v/v) TFA/H₂O/DCM (0.5 mL) for ca. 1 h. The solution containing thereleased material was concentrated and analyzed with LC/MS. UV (254 nm):97% @ 5.65 min. MS: m/e 171 (M−1).

Intermediate 14B Resin-bound 5-(4-Aminophenoxy)-2-nitroaniline

4-Aminophenol (4.71 g, 43.2 mmol) was dissolved in degassed DMF (108 mL)and bubbled with Ar for 10 min in a dry, 300-mL pear-shaped flask.Sodium hydride (60% in mineral, 1.78 g, 44.5 mmol) was added. Themixture was bubbled and stirred for an additional 15 min. Resin-bound5-chloro-2-nitroaniline 1 (4.3 g, theoretically 5.75 mmol) was added tothe now dark mixture. After the evolution of gas had minimized, theflask was stoppered and shaken at room temperature for ca. 4.5 days. Themixture was filtered and the salts washed away with water. The blackresin was washed with H₂O (3×), 1:1 DMF/H₂O (3×), DMF (3×), MeOH (3×)and DCM (3×). The reaction was repeated on the same resin batch the sameway. After drying in vacuo, a small sample (approx. 10 mg) was treatedwith 23:2:75 (v/v/v) TFA/H₂O/DCM (0.5 mL) for ca. 1 h. The solutioncontaining the released material was concentrated and analyzed withLC/MS. UV (254 nm): 90% @ 6.08 min. MS: m/e 244 (M−1).

Intermediate 14C (Library) Resin-bound5-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-2-nitroaniline

Intermediate 14B (approx. 224 mg, theoretically 0.273 mmol) was rinsedwith 1:1 (v/v) THF/DCM in a 25-mL Alltech tube. p-Nitrophenylchloroformate (551 mg, 2.73 mmol) and DIEA (476 μL, 2.73 mmol) in 1:1(v/v) THF/DCM (5.5 mL) was added. The mixture was shaken for 18–22 h.After draining, the resin was washed with 1:1 (v/v) THF/DCM (3–4×). Theheteroaryl amine (2.73 mmol) and DIEA (476 μL, 2.73 mmol) in DMF (5.5mL) were added. (Twice the equivalent of DIEA was used for the aminesthat were monohydrochloride salts.) The yellow mixtures were shaken forca. 16 h. and then drained. The resin was washed thoroughly with DMF(3×), 10:90 DIEA/DMF (10×), DMF (3×), 1:1 DMF/H₂O (3×), MeOH (3×), DCM(3×) to wash away most of the p-nitrophenol that slowly leached awayfrom the resin. After drying, a small sample (approx. 5 mg) was treatedwith 23:2:75 (v/v/v) TFA/H₂O/DCM (0.5 mL) for ca. 1 h. The solutioncontaining the released material was concentrated and analyzed withLC/MS.

Intermediate 14D (Library) Resin-Bound4-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-1,2-phenylenediamine

Intermediate 14C (theoretically 0.273 mmol) was soaked in NMP for atleast 30 min in a 25-mL Alltech tube. Tin (II) chloride dihydrate (1.85g, 8.20 mmol) in NMP (8.20 mL) was added and the mixture was shaken forca. 5.5 days. After filtration, the resin was washed with NMP (3×),30:70 ethylene diamine/NMP (10×), NMP (3×), MeOH (3×) and DCM (3×). Itwas dried under vacuum and a small sample (approx. 5 mg) was treatedwith 23:2:75 (v/v/v) TFA/H₂O/DCM (0.5 mL) for ca. 1 h. The solutioncontaining the released material was concentrated and analyzed withLC/MS.

Intermediate 14E (Library)1-Resin-bound-2-(Fmoc-amino)-6-(4-((heteroaryl)aminocarbonylamino)phenoxy)-1H-benzimidazoles

Intermediate 14D (theoretically 0.273 mmol) was rinsed with DMF in a25-mL Alltech tube. DIC (1.71 mL, 10.9 mmol) was added to a solution ofFmoc-NCS (1.54 g, 5.47 mmol) in DMF (5.5 mL) and the mixture wasimmediately added to the resin. The Alltech tube was vortexed vigorouslyfor ca. 6.75 days. The mixture was drained and the precipitate formedduring the reaction was washed away with DCM. The resin was then washedwith DCM (3×), DMF (3×), 1:1 DMF/H₂O (3×), MeOH (3×) and DCM (3×) anddried in vacuo. A small sample (approx. 5 mg) was treated with 23:2:75(v/v/v) TFA/H₂O/DCM (0.5 mL) for ca. 1 h. The solution containing thereleased material was concentrated and analyzed with LC/MS.

Intermediate 14F (Library)1-Resin-Bound-2-(R2-carbonylamino)-6-(4-((heteroaryl)aminocarbonylamino)phenoxy)-1H-benzimidazoles

Intermediate 14E (theoretically 0.0401 mmol) was treated with 20%piperidine in DMF (1 mL) in a 6-mL Alltech tube for 30 min. The mixturewas drained and the resin washed with DMF (3×). The piperidine treatmentand the succeeding DMF wash were repeated for a second time.

Coupling Procedure A (for acetic acid and 4-dimethylaminobutyric acidhydrochloride): To a mixture of DIEA (69.9 μL, 0.400 mmol) and EDC (38.5mg, 0.200 mmol) in DMF (0.67 mL) was added a solution of HOBt-H₂O (30.7mg, 0.200 mmol) and the acid (0.200 mmol) also dissolved in DMF (1.33mL). (The equivalent of DIEA was doubled for the butyric acid coupling.)The acid was activated for ca. 5 min. and then added to the deprotectedresin. The reaction mixture was vortexed for ca. 15 h. The solvent wasremoved by vacuum and the resin washed with DMF (3×), 1:1 DMF/H₂O (3×),MeOH (3×) and DCM (3×).

Coupling Procedure B (for 2-furoic and 2-(2-methoxyethoxy)acetic acids):To a solution of the acid (0.202 mmol) in DMF (0.67 mL) was addedHOBt-H₂O (30.9 mg, 0.202 mmol) in DMF (0.67 mL), DIEA (70.4 μL, 0.404mmol) and then HBTU (75.1 mg, 0.198 mmol) in DMF (0.67 mL). The reactionmixture was vortexed for ca. 20 h. After filtration, the resin waswashed with DMF (3×), 1:1 DMF/H₂O (3×), MeOH (3×) and DCM (3×).

Intermediate 15A 5-Amino-2-(3,4-diaminophenoxy)pyridine

2-Nitro-4-hydroxyaniline was reacted with 2-chloro-5-nitropyridine andK₂CO₃ in DMF at rt, followed by hydrogenation over Pd/C in MeOH,afforded the title compound; MS m/e 217 (M+1).

Intermediate 15B MethylN-(5-(5-aminopyridine-2-yl)-1H-benzimidazol-2-yl)carbamate

The title compound was obtained according to procedures for Intermediate3C and 3D, using the product of Intermediate 15A instead of3,4,4′-triaminodiphenylether; MS m/e 300 (M+1).

Example 1 Methyl N-(5-(4-((3-chlorophenyl) aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

A mixture of methyl (5-(4aminophenoxy)-1H-benzimidazol-2-yl)carbamate(Intermediate 3) (80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg,0.32 mmol) in dry THF (2 ml) was heated to 45° C. overnight. Aftercooling, diethyl ether was added to form a precipitate. The solid wascollected by filtration to provide the title compound (83 mg, 69%): ¹HNMR (DMSO-d₆) δ 11.60 (brs, 2H), 9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m,1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.32–7.24 (m, 2H), 7.01 (m, 2H), 6.93(d, 2H), 6.80 (dd, 1H) 3.75 (s, 3H); MS m/e 452 (M+1).

Examples 2–11, 14–16, 19–21, 40–78, 81, and 86 were prepared accordingto the procedures described above for Example 1. Intermediates 3, 3A,and 3B, were used or other precursors as indicated. The free basesobtained may be transformed into their pharmaceutically acceptable salts(e.g. HCl salts) by standard procedures known in the art.

Example 2 Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.61 (brs, 1H), 9.01 (s, 1H), 8.85 (s, 1H), 7.76 (s,1H), 7.08–7.52 (m, 8H), 6.90 (d, 1H), 6.53 (d, 1H), 5.35 (s, 1H), 3.71(s, 3H); MS m/e 502 (M+1).

Example 3 MethylN-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.65 (brs, 1H), 10.00 (s, 1H), 9.45 (s, 1H), 8.07(s, 2H), 7.59 (s, 1H), 7.31–7.48 (m, 4H), 7.05–7.20 (m, 4H), 3.72 (s,3H); MS m/e 570 (M+1).

Example 4 MethylN-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.61 (brs, 1H), 9.25 (s, 1H), 9.17 (s, 1H), 7.79 (s,1H), 7.40 (d, 2H), 7.16–7.36 (m, 6H), 7.10 (d, 1H), 7.05 (d, 1H), 5.72(s, 1H), 3.71 (s, 3H); MS m/e 513 (M+1).

Example 5 Methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.60 (brs, 1H), 9.13 (s, 1H), 9.05 (s, 1H), 7.40 (d,2H), 7.05–7.36 (m, 5H), 6.64 (d, 2H), 6.09 (s, 1H), 5.72 (s, 1H), 3.71(s, 3H), 3.67 (s, 6H); MS m/e 494 (M+1).

Example 6 Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.24 (brs, 1H), 9.32 (s, 1H), 8.93 (dd, 1H), 8.27(s, 1H), 7.79 (dd, 1H), 7.48–7.38 (m, 5H), 7.22 (dd, 2H), 7.12 (dd, 1H),3.75 (s, 3H), 2.35 (s, 3H); MS m/e 493 (M+1).

Example 7 MethylN-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.86 (brs, 1H), 8.72 (s, 1H), 8.58 (s, 1H),7.46–7.34 (m, 4H), 7.29 (dd, 1H), 7.23–7.14 (m, 4H), 7.08 (dd, 1H), 6.81(dd, 1H), 3.74 (s, 3H), 2.56 (q, 2H), 1.17 (t, 3H); MS m/e 462 (M+1).

Example 8 Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)amino carbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.81 (brs, 1H), 9.26 (s, 1H), 9.13 (dd, 1H), 8.99(s, 1H), 7.90 (m, 1H), 7.54 (dd, 1H), 7.46–7.38 (m, 4H), 7.21 (dd, 2H),7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 497 (M+1).

Example 9 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.70 (brs, 2H), 9.25 (s, 1H), 8.89 (d, 1H), 8.60(dd, 1H), 7.53–736 (m, 6H), 7.22 (d, 2H), 7.12 (dd, 1H), 3.75 (s, 3H);MS m/e 520 (M+1).

Example 9A Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamatemethanesulfonic acid

¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.97 (s, 1H), 8.60 (s, 1H), 7.58–7.48(m, 4H), 7.44–7.35 (m, 3H), 7.34 (d, 1H), 7.27 (dd, 1H), 3.85 (s, 3H),2.34 (s, 3H); MS m/e 520 (M+1).

Example 9B Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate sulfuricacid

¹H NMR (DMSO-d₆) δ 9.38(s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.58–7.48(m, 4H), 7.44–7.34 (m, 4H), 7.26 (dd, 1H), 3.84 (s, 3H); MS m/e 520(M+1).

Example 10 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ11.60 (brs, 2H), 9.13 (s, 1H), 8.85 (d, 1H), 8.62 (dd,1H), 7.49 (m, 1H), 7.44 (d, 2H), 7.40–7.35 (m, 2H), 7.01 (d, 1H), 6.94(d, 2H), 6.79 (dd, 1H) 3.74 (s, 3H); MS m/e 504 (M+1).

Example 11 MethylN-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ11.60 (brs, 2H), 8.71 (s, 1H), 8.67 (s, 1H), 7.42 (d,2H), 7.37 (d, 1H), 7.31–6.98 (m, 4H), 6.92 (d, 2H), 6.83–6.77 (m, 2H),3.75 (s, 3H), 2.57 (q, 2H), 1.17 (t, 3H); MS m/e 446 (M+1).

Example 12 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate

To a solution of methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate (Productof Example 9, 100 mg, 0.19 mmol) in acetic acid (2ml) was added mCPBA(92 mg, 0.53 mmol) in DCM (1 ml) and stirred over night. Aqueous NaHCO3solution was added and off-white solid was generated. Solid wascollected by filtration and washed with water and dried in vacuo. 80 mgof off-white compound was obtained: Yield 76.3%; ¹H NMR (DMSO-d₆) δ12.29(brs, 1H), 11.60 (brs, 1H), 9.70 (s, 1H), 9.07 (d, 1H), 8.56 (dd, 1H),7.95 (br, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.64–7.61 (m, 1H), 7.59–7.47(m, 2H), 7.45–7.40 (m, 1H), 3.78 (s, 3H); MS m/e 552 (M+1).

Example 13 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate

Reduced amount of mCPBA in Example 12 also afforded the title compound.¹H NMR (DMSO-d₆) δ12.12 (brs, 1H), 11.49 (br, 1H), 9.46 (s, 1H), 8.96(d, 1H), 8.58 (dd, 1H), 7.73 (s, 1H), 7.60 (s, 4H), 7.54–7.47 (m, 2H),7.43–7.38 (m, 1H), 7.34 (dd, 1H), 3.76 (s, 3H); MS m/e 536 (M+1).

Example 14 Methyl(5-(3-((3-Chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamatehydrochloride

¹H NMR (DMSO-d₆) δ 10.70 (brs, 1H), 8.82 (s, 1H), 8.79 (s, 1H), 7.64 (m,1H), 7.40 (d, 1H), 7.23 (m, 3H), 7.11 (m, 2H), 7.07 (m, 1H), 7.00 (d,1H), 6.82 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 452 (M+1).

Example 15 MethylN-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.67 (brs, 2H), 9.23 (s, 1H), 8.80 (s, 1H), 8.54 (d,1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.26 (t, 1H), 7.14 (d, 1H), 7.08 (d,2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 504 (M+1).

Example 16 MethylN-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ11.62 (br, 2H), 8.71 (s, 1H), 8.50 (s, 1H), 7.40 (d,1H), 7.25–7.15 (m, 5H), 7.09 (d, 2H), 6.81 (t, 2H), 6.55 (d, 1H), 3.75(s, 3H), 2.54 (q, 2H), 1.15 (t, 3H); MS m/e 446 (M+1).

Example 17 EthylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

The title compound was prepared by heating a mixture of the product ofExample 10 and NaOEt in ethanol:

¹H NMR (DMSO-d₆) δ 11.50 (brs, 2H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d,1H), 7.49 (t, 1H), 7.43 (d, 2H), 7.37 (m, 2H), 7.01 (s, 1H), 6.93 (d,2H), 6.79 (d, 1H), 4.21 (q, 2H), 1.27 (t, 3H); MS m/e 518 (M+1).

Example 18 t-ButylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

Utilizing the method described for preparing Intermediate 3, but using1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea instead of1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea afforded the titlecompound.

¹H NMR (DMSO-d₆) δ 11.80 (brs, 1H), 10.94 (brs, 1H), 9.12 (s, 1H), 8.85(s, 1H), 8.62 (dd, 1H), 7.50 (t, 1H), 7.42 (d, 2H), 7.37 (m, 2H), 7.00(brs, 1H), 6.91 (d, 2H), 6.76 (dd, 1H), 1.51 (s, 9H); MS m/e 546 (M+1).

Example 19 MethylN-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.80 (brs, 2H), 9.04 (s, 1H), 8.78 (s, 1H), 8.01 (s,1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.29 (d,1H), 7.00 (s, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 486(M+1).

Example 20 MethylN-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.60 (brs, 2H), 8.98 (s, 1H), 8.89 (s, 1H), 7.94 (s,1H), 7.54 (d, 1H), 7.49 (t, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.24 (t,1H), 7.14 (s, 1H), 7.09 (d, 2H), 6.83 (dd, 1H), 6.59 (d, 1H), 3.75 (s,3H); MS m/e 486 (M+1).

Example 21 MethylN-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ12.2–11.0 (brs, 2H), 8.61 (s, 1H), 8.59 (s, 1H), 7.45(m, 3H), 7.36 (d, 1H), 7.27 (d, 1H), 7.19 (t, 1H), 6.99 (m, 2H), 6.91(d, 2H), 6.78 (dd, 1H), 3.75 (s, 3H), 1.27 (s, 9H); MS m/e 474 (M+1).

Example 222-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole.

The title compound was prepared from intermediates 4, 5, and 6 describedabove. To a solution of4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phenylene-1,2-diamine(Intermediate 6) (1.5, 3.6 mmol) in MeOH (20 ml) was added cyanogenbromide (490 mg, 4.6 mmol). The reaction mixture was stirred for 1 h andthen washed with aq. NaOH. The product was extracted with AcOEt, driedover MgSO₄ and the solvent evaporated. Purification with SCX Ionexchange column chromatography (eluted first with MeOH then with aq. NH₃in MeOH) yielded the title compound (1.53 g, 96%); ¹H NMR (DMSO-d₆) δ10.63 (brs, 1H), 9.08 (s, 1H), 8.83 (s, 1H), 8.62 (d, 1H), 7.49 (t, 1H),7.40 (d, 2H), 7.38 (m, 1H), 7.05 (d, 1H), 6.89 (d, 2H), 6.74 (s, 1H),6.55 (d, 1H), 6.15 (s, 2H); MS m/e 446 (M+1).

Example 23(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3-(methanesulfonyl)-1H-benzimidazol-2-ylamine

To a mixture of 2-amino-5–4-((2-fluoro-5-trifluoromethylphenyl)aminocarbonylamino) phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol)(prepared according to similar procedures as described for Intermediates4, 5, and 6 and Example 22) and triethylamine (30 mg, 0.30 mmol) inDMF/CHCl₃ (3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26mmol). After stirring for 3 h at rt, the reaction mixture was washedwith water and extracted with CHCl₃. The organic layer was dried overMgSO₄ and evaporated. The crude material was purified with silica gelcolumn chromatography (AcOEt) to give the title compound (22.0 mg, 15%):¹H NMR (DMSO-d₆) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t,1H), 7.48 (d, 2H), 7.38 (m, 1H), 7.22 (d, 1H), 7.18 (s, 1H), 6.97 (d,2H), 6.87 (s, 1H), 6.86 (d, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).

Example 246-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine

Example 24 was prepared according to procedures similar to the onedescribed above in Example 23. They can be transformed into theirpharmaceutically acceptable salts (e.g. HCl salts) by standardprocedures. ¹H NMR (DMSO-d₆) δ9.18 (s, 1H)₁ 8.88 (d, 1H), 8.63 (dd, 1H),7.85 (d, 2H), 7.51–7.46 (m, 5H), 7.43–7.36 (m, 1H), 7.25 (d, 1H),7.14–7.11 (m, 3H), 6.94 (d, 2H), 6.84 (dd 1H), 2.38 (s 3H); MS m/e 600(M+1).

Example 25N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

To a mixture of 2-amino-5–4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole (prepared according tosimilar procedures as described for Intermediates 4, 5, and 6 andExample 22) (72 mg, 0.165 mmol), acetic acid (15 mg, 0.24 mmol) andtriethylamine (50 mg) in DMF was added HBTU (91 mg, 0.24 mmol) and HOBT(20 mg). The reaction mixture was stirred for 4 h, poured into water,washed and extracted with AcOEt The organic layer was dried over MgSO₄and evaporated. Purification of the residue by column chromatography onsilica gel (AcOEt as an eluant) afforded the title compound (28 mg,36%): ¹H NMR (DMSO-d₆) δ 11.99 (brs, 1H), 11.51 (br, 1H), 9.15 (s, 1H),8.87 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2h), 7.38 (m, 2H),7.04 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.15 (s, 3H); MS m/e 488(M+1).

Examples 26–35 and 87–102 were prepared according to procedures similarto that described above. They can be transformed into theirpharmaceutically acceptable salts (e.g. HCl salts) by standardprocedures.

Example 26N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)cyclopentamide

¹H NMR (DMSO-d₆) δ12.05 (brd, 1H), 11.51 (d, 1H), 9.13 (s, 1H), 8.85 (s,1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.39 (m, 2H), 6.99 (d.1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.93 (quint, 1H), 1.88 (m, 2H), 1.70(M, 4H), 1.57 (m, 2H); MS m/e 542 (M+1).

Example 27N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-fury)formamide

¹H NMR (DMSO-d₆) δ12.20 (brs, 2H), 9.16 (s, 1H), 8.88 (s, 1H), 8.62 (d,1H), 7.95 (s, 1H), 7.45 (m, 5H), 7.39 (m, 1H), 7.05 (s, 1H), 6.96 (d,2H), 6.86 (dd, 1H), 6.70 (m, 1H); MS m/e 540 (M+1).

Example 28N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylpentamide

¹H NMR (DMSO-d₆) δ 12.08 (brd, 1H), 11.51 (d, 1H), 9.13 (s, 1H), 8.85(s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.38 (m, 2H), 7.05(d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.44 (t, 2H), 1.53 (m, 2H), 0.90(d, 6H); MS m/e 544 (M+1).

Example 29N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-acetylamino)acetamide

¹H NMR (DMSO-d₆) δ 12.03 (brs, 1H), 11.58 (s, 1H), 9.14 (s, 1H), 8.85(s, 1H), 8.62 (d, 1H), 8.29 (t, 1H), 7.52 (t, 1H), 7.44 (d, 2H), 7.42(m, 1H), 7.39 (m, 1H), 7.05 (br, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 3.96(d, 2H), 1.90 (s, 3H); MS m/e 545 (M+1).

Example 30N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-aminoacetamidedihydrochloride

¹H NMR (DMSO-d₆) δ 9.76 (s, 1H), 9.15 (d, 2H), 8.62 (d, 1H), 8.40 (br,2H), 7.56 (d, 2H), 7.54 (d, 2H), 7.39 (m, 1H), 7.10 (s, 1H), 7.02 (m,1H), 7.01 (d, 2H), 3.97 (m, 2H); MS m/e 503 (M+1).

Example 31N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-methoxyacetamide

¹H NMR (DMSO-d₆) δ 12.09 (brs, 1H), 11.41 (br, 1H), 9.13 (s, 1H), 8.86(s, 1H), 8.62 (dd, 1H), 7.50 (m, 2H), 7.44 (d, 2H), 7.39 (m, 1H), 7.05(br, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.14 (s, 2H), 3.39 (s, 3H); MSm/e 518 (M+1).

Example 323-(N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionicacid

¹H NMR (DMSO-d₆) δ 12.10 (brs, 1H), 11.60 (brs, 1H), 9.22 (s, 1H), 8.92(s, 1H), 8.61 (dd, 1H), 7.60–7.40 (m, 3H), 7.44 (d, 2H), 7.05 (brs, 1H),6.93 (d, 2H), 6.80 (dd, 1H), 2.67 (t, 2H), 2.55 (t, 2H); MS m/e 546(M+1).

Example 33N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide

¹H NMR (DMSO-d₆) δ 12.11 (brs, 1H), 11.29 (brs, 1H), 9.15 (s, 1H), 8.86(d, 1H), 8.61 (dd, 1H), 7.43–7.50 (m, 5H), 6.98–7.14 (brm, 1H), 6.94 (d,2H), 6.82 (dd, 1H), 4.23 (s, 2H), 3.68–3.70 (m, 2H), 3.56–3.61 (m, 4H),3.49–3.47 (m, 2H), 3.24 (s, 3H); MS m/e 606 (M+1).

Example 34N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylaminophenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMSO-d₆) δ12.11 (brs, 1H), 11.28 (brs, 1H), 9.14 (s, 1H), 8.86(d, 1H), 8.61 (dd, 1H), 7.38–7.52 (m, 5H), 6.98–7.14 (brs, 1H), 6.94 (d,2H), 6.82 (dd, 1H), 4.22 (s, 2H), 3.68–3.71 (m, 2H), 3.51–3.54 (m, 2H),3.30 (s, 3H ); MS m/e 562 (M+1).

Example 35N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide

1H NMR (DMSO-d₆) δ 12.06 (d, 1H), 11.56 (brs, 1H), 9.13 (s, 1H), 8.85(s, 1H), 8.62 (s, 1H), 7.50 (t, 1H), 7.44 (d, 2H), 7.41 (m, 1H), 7.39(m, 1H), 7.17 (t, 1H), 7.04 (br, 1H), 6.97 (d, 2H), 6.81 (dd, 1H), 3.82(d, 2H), 1.40 (s, 9H); MS m/e 603 (M+1).

Example 36

N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamidedihydrochloride

The title compound was synthesized according to similar procedures asdescribed for Intermediates 7 and 8 and for Example 1 (13.0 mg 14%): ¹HNMR (DMSO-d₆) δ 12.42 (brs, 1H), 10.64 (brs, 1H), 9.97 (s, 1H), 8.66(dd, 1H), 8.11 (d, 1H), 7.68–7.61 (m, 1H), 7.60–7.48 (m, 3H), 7.47–7.41(m, 1H), 7.17 (d, 1H), 7.04 (dd, 1H), 2.24 (s, 3H); MS m/e 489 (M+1).

The compounds of Examples 37 to 39 were prepared according to proceduressimilar to that described for Example 36 above. They can be transformedinto their pharmaceutically acceptable salts (e.g. HCl salts) bystandard procedures.

Example 37 MethylN-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.1 (brm, 2H), 9.21 (s, 1H), 8.96 (d, 1H), 8.58(dd, 1H), 8.15 (d, 1H), 8.00 (dd, 1H), 7.52–7.48 (m, 1H), 7.41–7.38 (m,2H), 7.11 (d, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 3.75 (s, 3H); MS m/e 505(M+1).

Example 38N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)acetamide

hu 1H NMR (DMSO-d₆) δ 11.70 (brs, 2H), 9.17 (s, 1H), 8.88 (s, 1H), 8.17(d, 1H), 7.99 (s, 1H), 7.96 (d, 1H), 7.59 (d, 1H), 7.51 (t, 1H), 7.39(d, 1H), 7.31 (d, 1H), 7.11 (s, 1H), 6.92 (d, 1H), 6.83 (dd, 1H), 3.75(s, 3H); MS m/e 487 (M+1).

Example 39 MethylN-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.82 (brs, 1H), 11.30 (brs, 1H), 8.71 (d, 2H), 8.15(d, 1H), 7.95 (d, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 7.24 (d, 1H), 7.17(t, 1H), 7.09 (brs, 1H), 6.91 (d, 1H), 6.83–6.80 (m, 2H), 3.75 (s, 3H),2.56 (q, 2H), 1.17 (t, 3H); MS m/e 447 (M+1).

Example 40 MethylN-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.0 (brs, 2H), 9.11 (s, 1H), 8.93 (s, 1H), 7.84(t, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.31 (d, 1H), 7.22 (t, 1H), 7.13(d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e496 (m), 498 (M+2).

Example 41 MethylN-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 8.96 (s, 1H), 8.73 (s, 1H), 7.98(s, 1H), 7.55 (d, 1H), 7.46–7.42 (m, 1H), 7.43 (d, 2H), 7.37 (d, 1H),7.29 (d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H);MS m/e 518 (M+1).

Example 42 MethylN-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 9.31(s, 1H), 8.20 (s, 1H), 7.85(d, 1H), 7.42 (d, 2H), 7.36 (d, 1H), 6.99 (s, 1H), 6.91 (m, 3H), 6.78(dd, 1H), 6.48 (dd, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), δ; MSm/e 478 (M+1).

Example 43 MethylN-(5-(4-((2-chloro-5-(trifluoromethylphenyl)aminocarbonylaminophenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 9.53 (s, 1H), 8.65 (d, 1H), 8.57(s, 1H), 7.71 (d, 1H), 7.45 (d, 2H), 7.37 (m, 2H), 7.01 (s, 1H), 6.94(d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1), 522 (M+3).

Example 44 MethylN-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 9.13 (s, 1H), 8.80 (s, 1H), 8.11(d, 1H), 7.65–7.59 (m, 2H), 7.43 (d, 2H), 7.37 (d, 1H), 7.00 (d, 1H),6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 520 (M+1)), 522 (M+3).

Example 45 MethylN-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.50 (s, 1H), 8.42 (s, 1H), 8.33(m, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.38 (d, 1H), 7.08 (dd, 1H), 7.01(d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 486 (M+1).

Example 46 MethylN-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.16 (m, 2H), 8.97 (s, 1H), 7.90(m, 1H), 7.55 (t, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.94(d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 481 (M+1).

Example 47 MethylN-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.22 (s, 1H), 8.96 (d, 1H), 8.23(s, 1H), 7.79 (dd, 1H), 7.47 (m, 1H), 7.46 (d, 2H), 7.38 (d, 1H), 7.01(d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H), 2.37 (s, 3H); MS m/e477 (M+1).

Example 48 MethylN-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 8.67 (s, 1H), 8.64 (s, 1H), 7.46(t, 1H), 7.41 (d, 2H), 7.36 (d, 1H), 7.21 (t, 1H), 7.13 (d, 1H), 6.99(d, 1H), 6.92 (d, 2H), 6.84 (d, 1H), 6.78 (dd, 1H), 3.74 (s, 3H), 2.45(s, 3H); MS m/e 464 (M+1).

Example 49 MethylN-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.02 (s, 1H), 8.83 (s, 1H), 7.97(s, 1H), 7.67 (d, 1H), 7.49 (t, 1H), 7.43 (d, 2H), 7.42 (t, 1H), 7.37(d, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e443 (M+1).

Example 50 MethylN-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.21 (s, 1H), 8.87 (s, 1H), 7.70(s, 1H), 7.61 (d, 1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.22 (d, 1H), 7.00(d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 504 (M+1).

Example 51 MethylN-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamatehydrochloride

¹H NMR (DMSO-d₆) δ 9.82 (s, 1H), 6.69 (s, 1H), 8.62 (d, 1H), 7.71 (d,1H), 7.46 (d, 2H), 7.42–7.36 (m, 3H), 7.21 (d, 2H), 7.12 (dd, 1H), 3.75(s, 3H); MS m/e 536 (M+1), 538 (M+3).

Example 52 MethylN-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamatehydrochloride

¹H NMR (DMSO-d₆) δ 9.67 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 7.70 (d,1H), 7.41 (d, 1), 7.36 (dd, 1H), 7.27 (t, 1H), 7.18 (d, 1H), 7.09 (d,1H), 7.03 (t, 1H), 6.84 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e520 (M+1), 522 (M+3).

Example 53 MethylN-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 8.91 (s, 1H), 8.64 (s, 1H), 8.15(t, 1H), 7.65(d, 1H), 7.55 (d, 1H), 7.44–7.40 (m, 3H), 7.37 (d, 1H),7.00 (s, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 4.31 (q, 2H), 3.74 (s, 3H),1.32 (t, 3H); MS m/e 490 (M+1).

Example 54 MethylN-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

Hydrolysis of the product of Example 53 with NaOH gave the titlecompound. ¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 8.97 (brs, 1H), 8.77(brs, 1H), 8.12 (s, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7.44 (d, 2H), 7.38(m, 2H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e462 (M+1).

Example 55 MethylN-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamatehydrochloride

¹H NMR (DMSO-d₆) δ 9.56 (s, 1H), 8.66 (s, 1H), 7.96 (d, 1H), 7.58 (d,1H), 7.51 (d, 2H), 7.12–7.06 (m, 3H), 7.01 (d, 2H), 6.79 (m, 1H), 3.86(s, 3H), 2.27 (s, 3H); MS m/e 450 (M+1).

Example 56 MethylN-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.0 (brs, 2H), 9.09 (s, 1H), 8.71 (s, 1H), 8.04(m, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.29 (m, 1H), 7.00 (d, 1H), 6.93(d, 2H), 6.82 (m, 1H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 454 (M+1).

Example 57 MethylN-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.60 (s, 1H), 8.46 (s, 1H), 8.30(d, 1H), 7.49 (d, 1H), 7.45–7.39 (m, 4H), 7.21 (d, 2H), 7.13 (dd, 1H),7.09 (dd, 1H), 3.75 (s, 3H); MS m/e 502 (M+1), 504 (M+3).

Example 58 MethylN-(5-(3-((3-trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.02 (s, 1H), 8.94 (s, 1H), 7.90(s, 1H), 7.52 (d, 1H), 7.44–7.40 (m, 2H), 7.30–7.21 (m, 2H), 7.12–7.07(m, 3H), 6.84 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 518 (M+1).

Example 59 MethylN-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.5 (brs, 2H), 7.78 (s, 1H), 7.41 (d, 1H),7.30–7.00 (m, 9H), 6.83 (dd, 1H), 6.57 (dd, 1H), 3.75 (s, 3H); MS m/e496 (M), 498 (M+2).

Example 60 MethylN-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.5 (brs, 2H), 8.94 (s, 1H), 8.91 (s, 1H), 7.39(m, 3H), 7.30–7.21 (m, 2H), 7.19 (t, 1H), 7.11–7.00 (m, 7H), 6.83 (dd,1H), 6.59 (d, 1H), 6.54 (d, 1H) 3.75 (s, 3H); MS m/e 510 (M+1).

Example 61 MethylN-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 8.94 (s, 1H), 8.91 (s, 1H),7.44–7.40 (m, 3H), 7.29 (d, 2H), 7.23 (t, 1H), 7.14 (t, 1H), 7.07 (s,2H), 6.82 (dd, 1H), 6.57 (dd, 1H), 3.75 (s, 3H), δ; MS m/e 452 (M+1).

Example 62 MethylN-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.0 (brs, 2H), 8.53 (s, 1H), 8.42 (s, 1H), 7.40(d, 2H), 7.36 (d, 1H), 7.34 (d, 2H), 6.99 (d, 1H), 6.90 (d, 2H), 6.86(d, 2H), 6.78 (dd, 1H), 3.74 (s, 3H), 3.71 (s, 3H); MS m/e 448 (M+1).

Example 63 MethylN-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 8.66 (s, 1H), 8.61 (s, 1H),7.46–7.40 (m, 5H), 7.36 (d, 1H), 7.11 (t, 2H), 7.00 (d, 1H), 6.91 (d,2H), 6.78 (dd, 1H), 3.74 (s, 3H), δ; MS m/e 436 (M+1).

Example 64 MethylN-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-benzthiazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 10G was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 12.05 (brs, 1H), 9.18 (s, 1H), 8.87 (d, 1H), 8.62(dd, 1H), 7.66 (d, 1H), 7.60 (s, 1H), 7.50 (m, 1H), 7.47 (d, 2H), 7.38(m, 1H), 7.07 (dd, 1H), 7.00 (d, 2H), 3.77 (s, 3H); MS m/e 521 (M+1).

Example 65 MethylN-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethylphenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamatehydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 10H was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 12.39 (brs, 1H), 9.27 (brs, 1H), 8.91 (d, 1H), 8.62(dd, 1H), 7.67 (d, 1H), 7.50 (d, 2H), 7.50 (m, 1H), 7.39 (m, 1H), 7.32(d, 1H), 7.05 (d, 2H), 3.78 (s, 3H); MS m/e 599, 601 (M+1).

Example 66 MethylN-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 8J was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.22 (brs, 1H), 8.92 (brs, 1H), 8.61 (d, 1H), 7.50(m, 1H), 7.45 (d, 2H), 7.43–7.36 (m, 2H), 7.15 (d, 1H), 6.96 (d, 2H),6.83 (dd, 1H), 3.62 (s, 3H), 3.46 (s, 3H); MS m/e 518 (M+1).

Example 67 MethylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 8C was used as a precursor in lieu of Intermediate 1.

¹H NMR (chloroform-d₁) δ 8.65 (brd, 1H), 7.43 (d, 2H), 7.22 (m, 1H),7.14(m, 1H), 7.12 (d, 1H), 6.99–6.90 (m, 4H), 3.78 (s, 3H), 3.59 (s, 3H); MSm/e 518 (M+1).

Example 68 MethylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3a-aza-2-indolyl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9K was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 10.28 (brs, 1H), 9.26 (s, 1H), 8.95 (s, 1H), 8.60(dd, 1H), 8.47 (d, 1H), 7.87 (s, 1H), 7.48 (m, 1H), 7.47 (d, 2H), 7.42(d, 1H), 7.38 (m, 1H), 7.05 (dd, 1H), 7.02 (d, 2H), 3.68 (s, 3H); MS m/e504 (M+1).

Example 69 MethylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diazaindolin-2-yl)carbamatedihydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9D was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.21 (s, 1H), 8.89 (d, 1H), 8.63 (dd, 1H), 7.79 (d,1H), 7.49 (d, 1H), 7.47 (d, 2H), 7.38 (m, 1H), 7.05 (d, 2H), 6.73 (d,1H), 3.76 (s, 3H); MS m/e 505 (M+1).

Example 70 MethylN-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 8K was used as a precursor in lieu of Intermediate 1.

¹H NMR (chloroform-d₁) δ 9.02 (brs, 1H), 8.59 (dd, 1H), 8.48 (brs, 1H),7.38 (d, 2H), 7.17 (d, 1H), 7.13 (m, 1H), 7.03 (dd, 1H), 6.86 (d, 2H),6.84 (d, 1H), 6.76 (dd, 1H), 4.06 (t, 2H), 3.79 (s, 3H), 2.70 (t, 2H),2.32 (s, 6H); MS m/e 573 (M−1).

Example 71 MethylN-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 8L was used as a precursor in lieu of Intermediate 1.

¹H NMR (chloroform-d₁) δ 8.66–8.59 (br, 2H), 8.15 (d, 1H), 7.38 (d, 2H),7.19 (d, 1H), 7.18 (m, 1H), 7.07 (dd, 1H), 6.90 (d, 2H), 6.86 (d, 1H),6.81 (dd, 1H), 4.09 (t, 2H), 3.82 (s, 3H), 3.64 (brs, 4H), 2.70 (t, 2H),2.50 (brs, 4H); MS m/e 615 (M−1).

Example 72 MethylN-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamatedihydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9D was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.65 (d, 1H), 8.61 (s, 1H), 7.80 (d,1H), 7.22 (d, 1H), 7.48 (d, 2H), 7.37 (dd, 1H), 7.05 (d, 2H), 6.73 (d,1H), 3.76 (s, 3H); MS m/e 521 (M+1), 523 (M+3).

Example 73 MethylN-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamatedihydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9E was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.64 (d, 1H), 8.60 (s, 1H), 8.09 (d,1H), 7.72 (d, 1H), 7.49 (d, 2H), 7.47 (d, 1H), 7.37 (dd, 1H), 7.01 (d,2H), 3.78 (s, 3H); MS m/e 521, 523 (M+1).

Example 74 MethylN-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamatedihydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9D was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.56 (s, 1H), 8.46 (s, 1H), 8.34 (d, 1H), 7.80 (d,1H), 7.51 (d, 1H), 7.47 (d, 2H), 7.09 (dd, 1H), 7.05 (d, 2H), 6.73 (d,1H), 3.76 (s, 3H); MS m/e 487 (M+1), 489 (M+3).

Example 75 MethylN-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamatedihydrochloride

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9E was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 9.22 (s, 1H), 8.89 (d, 1H), 8.61 (dd, 1H), 8.08 (s,1H), 7.53–7.42 (m, 4H), 7.38 (m, 1H), 7.01 (d, 2H), 3.78 (s, 3H); MS m/e505 (M+1).

Example 76 MethylN-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 10G was used as a precursor in lieu of Intermediate 1.

¹H NMR (DMSO-d₆) δ 12.06 (s, 1H), 9.57 (s, 1H), 8.65 (d, 1H), 8.59 (s,1H), 7.22 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.50 (t, 1H), 7.48 (t,1H), 7.37 (dd, 1H), 7.09 (dd, 1H), 7.02 (t, 1H), 7.00 (t, 1H), 3.77 (s,3H), δ; MS m/e 537 (M+1), 539 (M+3).

Example 776-(4-((2-Fluoro-5-(trifluoromethylphenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a,5-triazacarbazol-2-one

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 9I was used as a precursor in lieu of Intermediate 3.

¹H NMR (DMSO-d₆) δ 9.22 (d, 1H), 8.92 (s, 1H), 8.62 (d, 1H), 7.83 (d,1H), 7.50 (m, 1H), 7.48 (d, 2H), 7.38 (m, 1H), 7.07 (d, 2H), 6.71 (d,1H), 4.12 (t, 2H), 2.83 (t, 2H); MS m/e 501 (M+1).

Example 78 MethylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcarbonyl)-1H-benzimidazol-2-yl)carbamate

This example was prepared according to the procedure of Example 1 exceptthat Intermediate 11D was used as a precursor in lieu of Intermediate 3.

¹H NMR (DMSO-d₆) δ 12.5–11.2 (brs, 2H), 9.59 (s, 1H), 9.04 (s, 1H), 8.62(d, 1H), 7.83 (brs, 1H), 7.75 (d, 2H), 7.65 (d, 2H), 7.55–7.50 (m, 3H),7.44 (m, 1H), 3.78 (s, 3H); MS m/e 516 (M+1).

Example 79 MethylN-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate

The title compound was prepared following the procedure for Example 12except that the product of Example 57 was used as a precursor.

¹H NMR (DMSO-d₆) δ 12.4–11.3 (brs, 2H), 9.80 (s, 1H), 8.52 (s, 1H), 8.29(d, 1H), 7.73 (s, 1H), 7.60 (s, 4H), 7.51 (m, 1H), 7.50 (d, 1H), 7.34(dd, 1H), 7.11 (dd, 1H), 3.76 (s, 3H); MS m/e 518 (M+1).

Example 80 2-(Dimethylamino)ethylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

Heating of a mixture of Example 10 and NaH, 2-(dimethylamino)ethanolgave the title compound:

¹H NMR (DMSO-d₆) δ 11.62 (br, 2H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d,1H), 7.54–7.34 (m, 5H), 7.01 (d, 1H), 6.93 (d, 2H), 6.78 (dd, 1H), 4.25(dd, 2H), 2.54 (t, 2H), 2.20 (s, 6H); MS m/e 561 (M+1).

Example 81 BenzylN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

Following the method for Example 1 using Intermediate 3D instead ofIntermediate 3 afforded the title compound.

¹H NMR (DMSO-d₆) δ 11.73 (br, 2H), 9.17 (s, 1H), 8.87 (s, 1H), 8.62 (d,1H), 7.53–7.33 (m, 10H), 7.01 (d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 5.24(s, 2H); MS m/e 580 (M+1).

Example 825-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1(methanesulfonyl)-1H-benzimidazol-2-ylamine

To a mixture of2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole(90 mg, 0.20 mmol) (prepared according to similar procedures asdescribed for Intermediates 4, 5, and 6 and Example 22) andtriethylamine (30 mg, 0.30 mmol) in DMF/CHCl₃ (3 ml/1 ml) was addedmethanesulfonyl chloride (30 mg, 0.26 mmol). After stirring for 3 h atrt, the reaction mixture was washed with water and extracted with CHCl₃.The organic layer was dried over MgSO₄ and evaporated. The crudematerial was purified with silica gel column chromatography (AcOEt) togive the product of Example 23 (11.0 mg, 11%) and the title compound (34mg, 25%): ¹H NMR (DMSO-d₆) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H),7.51 (d, 1H), 7.47 (d, 1H), 7.46 (d, 2H), 7.38 (m, 1H), 7.02 (brs, 2H),6.97 (d, 2H), 6.82 (d, 1H), 6.70 (dd, 1H), 3.49 (s, 3H); MS m/e 524(M+1).

Example 83N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)methanesulfonamide

2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole(the product of Example 22–600 mg) and methanesulfonyl chloride (5equiv.) in pyridine was stirred at room temperature for 2 days. Theresulting mixture was treated with K₂C₀₃ (10 equiv.) and H₂O (10 mL) andMeOH (10 mL), and heated at 60 C. for 7 days. The crude solid wascollected by filtration. Recrystallization from hot MeOH afforded thetitle compound (280 mg, 40%);

¹H NMR (DMSO-d₆) δ 11.69 (br, 2H), 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d,1H), 7.54–7.43 (m, 3H), 7.41–7.36 (m, 1H), 7.23 (d, 1H), 6.97 (d, 2H),6.86 (d, 1H), 6.80 (dd, 1H), 2.92 (s, 3H); MS m/e 524 (M+1).

Example 845-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine

The title compound was prepared following for Example 24. The productsof Example 24 and 84 are separated by columnchromatography.

¹H NMR (DMSO-d₆) δ 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.93 (d,2H), 7.62 (d, 1H), 7.53–7.42 (m, 5H), 7.41–7.36 (m, 1H), 7.25 (br, 2H),6.96 (d, 2H), 6.70 (d, 1H), 6.66 (dd, 1H), 2.37 (s, 3H); MS m/e 600(M+1).

Example 85N-(5-(4-((2-Fluoro-5-(trifluoromethy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylbenzenesulfonamide

To a mixture of Intermediate 6 (105 mg, 0.25 mmol) and N′,N″-bis-p-tolylsulfonyl-S-methylisothiourea (100 mg, 0.25 mmol; prepared from p-toluenesulfonamide, cf. J.Org.Chem., 1998, 53, 3120–3122; Zh.Org.Khim., 1975,11, (3), 574–576) in THF (3ml) was added acetic acid (0.5 ml) andstirred for 4 days at 90° C. Reaction mixture was treated with SPE (NH₂)tube (washed with MeOH and eluted with NH₃/MeOH), NH3/MeOH eluent wascollected and purified by column chromatography (hexane-AcOEt, 1:1) anddesired compound was obtained as off-white solid. (2.3 mg, yield 1.53%)

¹H NMR (DMSO-d₆) δ 11.89 (br, 1H), 11.84 (br, 1H), 9.16 (s, 1H), 8.85(s, 1H), 8.61 (d, 1H), 7.76 (d, 2H), 7.53–7.43 (m, 3H), 7.41–7.36 (m,1H), 7.31 (d, 2H), 7.24 (d, 1H), 6.97 (d, 2H), 6.86 (d, 1H), 6.82 (dd,1H), 2.33 (s, 3H); MS m/e 600 (M+1).

Example 86N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)methanesulfonamide

A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate (47.4 mg, 0.23mmol) and Intermediate 10D (72 mg, 0.21 mmol) in THF (3 ml) was stirredover night at 45° C. The reaction mixture was cooled to room temperatureand ether was added and a pale brown solid was generated. The solid wascollected by filtration and washed with ether and dried in vacuo. 55 mgof desired compound was obtained.

(50% yield)

¹H NMR (DMSO-d₆) δ 12.95 (br, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.61 (d,1H), 7.54–7.44 (m, 4H), 7.41–7.36 (m, 1H), 7.30 (d, 1H), 7.05 (dd, 1H),6.99 (d, 2H), 2.99 (s, 3H); MS m/e 541 (M+1).

Examples 87–102 were prepared according to procedure similar to Example25.

Example 87N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide

¹H NMR (DMSO-d₆) δ 12.20 (brs, 2H), 9.15 (s, 1H), 8.86 (d, 1H), 8.62(dd, 1H), 8.08 (d, 2H), 7.44–7.53 (m, 4H), 7.35–7.42 (m, 1H), 7.22–7.34(brs, 1H), 7.08 (d, 1H), 6.96 (d, 2H), 6.86 (dd, 1H), 6.64–6.76 (brs,1H), 3.54 (s, 2H), 2.25–2.48 (brs, 4H), 2.18 (s, 4H), 1.76 (s, 3H); MSm/e 663 (M+2).

Example 88N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide

¹H NMR (DMSO-d₆) δ 12.04 (brd, 1H), 11.57 (brd, 1H), 9.15 (s, 1H), 8.86(d, 1H), 8.62 (dd, 1H), 8.50 (d, 1H), 8.40 (dd, 1H), 7.69 (d, 1H),7.35–7.53 (m, 5H), 7.32 (dd, 1H), 7.03 (d, 1H), 6.93 (d, 2H), 6.80 (dd,1H), 2.96 (t, 2H), 2.80 (t, 2H); MS m/e 579 (M+1).

Example 89N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-5-benzimidazolecarboxamide

¹H NMR (DMSO-d₆) δ 12.80 (brs, 1H), 12.40 (brs, 2H), 9.16 (s, 1H), 8.88(s, 1H), 8.62 (d, 1H), 8.45 (brs, 1H), 8.39 (dd, 1H), 8.01 (d, 1H), 7.69(brs, 1H), 7.44–7.53 (m, 4H), 7.36–7.41 (m, 1H), 7.09 (brs, 1H), 6.96(d, 2H), 6.85 (dd, 1H); MS m/e 590 (M+1).

Example 90N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide

¹H NMR (DMSO-d₆) δ 12.26 (brs, 2H), 9.17 (s, 1H), 8.88 (s, 1H), 8.62 (d,1H), 8.22 (d, 2H), 7.77 (d, 2H), 7.54 (t, 2H), 7.42–7.52 (m, 4H),7.36–7.41 (m, 1H), 7.08 (brs, 1H), 6.97 (d, 2H), 6.86 (dd, 1H), 6.33 (t,2H); MS m/e 615 (M+1).

Example 91N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide

¹H NMR (DMSO-d₆) δ 12.40 (brs, 2H), 9.17 (s, 1H), 8.86 (d, 1H), 8.62(dd, 1H), 8.43 (s, 1H), 8.27 (d, 2H), 8.05 (d, 1H), 7.80–7.96 (m, 3H),7.45–7.54 (m, 3H), 7.33–7.42 (m, 1H), 7.16 (s, 1H), 7.07 (brs, 1H), 6.98(d, 2H), 6.88 (dd, 1H); MS m/e 616 (M+1).

Example 92N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(dimethylamino)butylamide

¹H NMR (DMSO-d₆) δ 12.02 (br, 1H), 11.56 (br, 1H), 9.18 (s, 1H), 8.90(s, 1H), 8.62 (s, 1H), 7.53–7.35 (m, 5H), 7.16–6.97 (m, 1H), 6.93 (d,2H), 6.80 (dd, 1H), 2.45 (t, 2H), 2.24 (t, 2H), 2.13 (s, 6H), 1.75 (m,2H); MS m/e 559 (M+1).

Example 93N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-pyridinecarboxamide

¹H NMR (DMSO-d₆) δ 12.41 (br, 2H), 9.26 (d, 1H), 9.16 (s, 1H), 8.87 (s,1H), 8.74 (s, 1H), 8.62 (dd, 1H), 8.43 (m, 1H), 7.57–7.42 (m, 5H),7.42–7.36 (m, 1H), 7.05 (d, 1H), 6.98 (d, 2H), 6.88 (dd, 1H); MS m/e 551(M+1).

Example 94N-(5-(4-((2-Fluoro-5-(trifluoromethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-tetrahydrofurancarboxamide

¹H NMR (DMSO-d₆) δ 12.08 (br, 1H), 11.26 (br, 1H), 9.14 (s, 1H), 8.86(s, 1H), 8.62 (d, 1H), 7.53–7.41 (m, 4H), 7.41–7.35 (m, 1H), 7.06(br,1H), 6.94 (d, 2H), 6.83 (dd, 1H), 4.53 (dd, 1H), 3.99 (q, 1H), 3.83 (q,1H), 2.28–2.18 (m, 1H), 2.04–1.83 (m, 3H); MS m/e 544 (M+1).

Example 95N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-indole-3-carboxamide)

¹H NMR (DMSO-d₆) δ 12.25 (brs, 1H), 11.77 (s, 1H), 9.18 (s, 1H), 8.88(d, 1H), 8.62 (dd, 1H), 7.70 (d, 1H), 7.60 (brs, 1H), 7.43–7.55 (m, 6H),7.35–7.41 (m, 1H), 7.25 (t, 1H), 7.05–7.12 (m, 2H), 6.97 (d, 2H), 6.86(dd, 1H); MS m/e 589 (M+1).

Example 96N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide

¹H NMR (DMSO-d₆) δ 12.17 (brs, 2H), 9.14 (s, 1H), 8.85 (d, 1H), 8.61(dd, 1H), 7.36–7.53 (m, 5H), 7.01 (d, 1H), 6.96 (d, 2H), 6.85 (dd, 1H),5.49 (s, 2H), 3.30–3.40 (m, 4H, overlap with d6-DMSO water peak),1.88–1.97 (m, 4H); MS m/e 625 (M+1).

Example 97N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1methyl-1H-imidazol-4-yl)acetamide

¹H NMR (DMSO-d₆) δ 12.10 (brs, 1H), 11.85 (brs, 1H), 9.39 (s, 1H), 9.07(dd, 2H), 7.62–7.84 (m, 7H), 7.33 (s, 1H), 7.21 (d, 2H), 7.11 (dd, 1H),3.99 (s, 5H); MS m/e 568 (M+1).

Example 98N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-imidazole-4-carboxamide)dihydrochloride

¹H NMR (DMSO-d₆) δ 9.74 (s, 1H), 9.13 (s, 1H), 8.62 (d, 2H), 8.24 (s,1H), 7.60 (d, 1H), 7.53 (d, 2H), 7.48 (d, 1H), 7.40 (m, 1H), 7.17 (d,1H), 7.08 (m, 1H), 7.04 (d, 2H), 3.88 (s, 3H); MS m/e 540 (M+1).

Example 99N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)benzamide

¹H NMR (DMSO-d₆) δ 12.6–12.2 (brs, 2H), 9.15 (s, 1H), 8.87 (d, 1H), 8.62(dd, 1H), 8.13 (d, 2H), 7.95 (s, 2H), 7.64–7.50 (m, 4H), 7.45 (d, 2H),7.39 (brm, 1H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 550 (M+1).

Example 100N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-thiophenecarboxamide

¹H NMR (DMSO-d₆) δ 12.23 (br, 2H), 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d,1H), 8.02 (br, 1H), 7.84 (br, 1H), 7.54–7.34 (m, 5H), 7.20 (t, 1H),7.03(br, 1H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 556 (M+1).

Example 101N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide

¹H NMR (DMSO-d₆) δ 11.90–12.25 (brd, 1H), 10.90–11.30 (brs, 1H), 9.13(s, 1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.33–7.53 (m, 5H), 6.97–7.18 (brd,1H), 6.93 (d, 2H), 6.81 (dd, 1H), 3.26 (s, 2H), 2.5–42.62 (bs, 4H),2.28–2.42 (bs, 4H), 2.16 (s, 3H); MS m/e 584 (M−1).

Example 102N-(5-(4-((2-Fluoro-5-(trifluoromethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(dimethylamino)acetamide

¹H NMR (DMSO-d₆) δ 12.10 (brs, 1H), 9.14 (s, 1H), 8.85 (d, 1H), 8.62(dd, 1H), 7.35–7.53 (m, 6H), 6.96 (brs, 1H), 6.95 (d, 2H), 6.85 (dd,1H), 3.60–3.80 (brs, 2H), 2.55–2.67 (brs, 6H); MS m/e 529 (M−1).

Example 103

Prepared as described by the coupling reaction in Example 25 using1-piperidine propionic acid. Using these reaction conditions,elimination of piperidine followed by cyclization to the tworegioisomeric products in a 1:1 ratio occurred in situ without isolationof the intermediates.

¹H NMR (DMSO-d₆) δ 11.45 (brs, 1H), 11.42 (brs, 1H), 9.12 (s, 2H), 8.84(d, 2H), 8.61 (dd, 2H), 7.35–7.53 (m, 10H), 7.15 (d, 1H), 7.03 (d, 1H),6.93 (d, 2H), 6.91 (d, 2H), 6.85 (dd, 1H), 6.80 (dd, 1H), 4.25 (t, 2H),4.21 (t, 2H), 2.89 (t, 2H), 2.86 (t, 2H); MS m/e 500 (M+1).

The two regioisomers were separated by successive recrystallizationsfrom 2-butanone followed by methanol.

Example 103A6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one

¹H NMR (DMSO-d₆) δ 9.16 (s, 1H), 8.88 (d, 1H), 8.61 (d, 1H), 7.35–7.53(m, 5H), 7.15 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 4.21 (t, 2H), 2.86(t, 2H); MS m/e 500 (M+1).

Example 103B7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one

¹H NMR (DMSO-d₆) δ 11.42 (brs, 1H), 9.17 (s, 1H), 8.90 (s, 1H), 8.61(dd, 1H), 7.35–7.53 (m, 5H), 7.03 (d, 1H), 6.91 (d, 2H), 6.84 (dd, 1H),4.25 (t, 2H), 2.89 (t, 2H); MS m/e 500 (M+1).

Example 1042-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole

To a stirred solution ofN-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(N-4-methyl-1-piperazino)acetamide(the product of Example 101, 150 mg, 0.26 mmol) in dry THF (10 ml) undernitrogen was added dropwise a solution of lithium aluminium hydride inTHF (5 ml of a 1M solution, 5 mmol). The reaction was stirred at roomtemperature for 5h and then quenched by slow dropwise addition of ethylacetate, followed by methanol and water. The resulting white precipitatewas filtered off through a celite pad and washed well with methanol. Thefiltered solution was evaporated to dryness and partioned between ethylacteate and water. The aqueous phase was further extracted by ethylacetate three times and then combined ethyl acetate solutions were driedover magnesium sulfate and concentrated to give the crude product as anoil. Purification of the crude material by column chromatography(eluting with AcOEt and incremental amounts of methanolic ammonia up to10%) afforded the product as an oil (86 mg, 58% yield).

¹H NMR (DMSO-d₆) δ 10.80 (brs, 1H), 9.10 (s, 1H), 8.84 (d, 1H), 8.61(dd, 1H), 7.49 (t, 1H), 7.35–7.43 (m, 4H), 7.08 (d, 1H), 6.88 (d, 2H),6.70 (d, 1H), 6.41 (brs, 1H), 2.25–2.45 (m, 4), 2.15 (s, 4H), 1.76 (s,7H); MS m/e 572 (M+1).

Example 1052-(2-(Dimethylamino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole

The title compound was prepared as described in Example 104 using theproduct of Example 102;

¹H NMR (DMSO-d₆) δ 10.75 (brs, 1H), 9.10 (s, 1H), 8.85 (d, 1H), 8.61(dd, 1H), 7.49 (t, 1H), 7.34–7.44 (m, 4H), 7.08 (d, 1H), 6.88 (d, 2H),6.55 (dd, 1H), 6.43 (brs, 1H), 3.53 (t, 2H, overlap with d6-DMSO waterpeak), 2.44 (t, 2H), 3.19 (s, 6H); MS m/e 517 (M+1).

Example 1062-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole

To a stirred solution of thiophosgene (1.47 g, 12.8 mmol) in acetone (10ml) and dichloromethane (10 ml), cooled in an ice bath under nitrogen,was added dropwise a solution of 1-(3-aminopropyl)-4-methylpiperazine(1.0 g, 6.4 mmol) in acetone (5 ml) and dichloromethane (5 ml) over 10minutes. The reaction was stirred at room tempertaure for 3h and thendiluted with dichloromethane (50 ml) and washed with aqueous sodiumbicarbonate solution (25 ml). The aqueous phase was further extracted bydichloromethane twice and then combined dichloromethane solutions weredried over magnesium sulfate and concentrated to give a brown oil (0.37g, 1.86 mmol, 0.29% yield) which was used without purification. Thecrude oil was dissolved in acetonitrile (30 ml) and4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phenylene-1,2-diamine(intermediate 6) (0.20 g, 0.47 mmol) was added. The stirred reaction washeated to reflux for 24 hours. On cooling, the reaction solution wasdecanted off to leave behind an insoluble dark oil residue. Theacetonitrile was evaporated off to give a crude oil. Purification of thecrude material was achieved by two column chromatographic separations.The first eluting with dichloromethane and incremental amounts ofmethanolic ammonia up to 15%, and the second eluting with AcOEt andincremental amounts of methanolic ammonia up to 15%, to afford theproduct as an oil (79 mg, 28% yield) which solidified on standing.

¹H NMR (DMSO-d₆) δ 10.76 (brs, 1H), 9.09 (s, 1H), 8.83 (d, 1H), 8.61(dd, 1H), 7.49 (t, 1H), 7.35–7.43 (m, 3H), 7.07 (d, 1H), 6.88 (d, 2H),6.76 (d, 1H), 6.63 (brs, 1H), 6.56 (brs, 1H), 2.22–2.43 (m, 10H), 2.15(s, 4H), 1.65–1.78 (m, 3H); MS m/e 586 (M+1).

Example 107 MethylN-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate

The title compound was prepared following the procedure for Example 12using the compound of Example 37.

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.42 (s, 1H), 9.06 (s, 1H), 8.68(s, 1H), 8.53 (d, 1H), 7.53 (t, 1H), 7.45 (brs, 1H), 7.39 (d, 1H), 7.30(d, 1H), 7.11 (d, 1H), 7.02 (s, 1H), 6.80 (d, 1H), 3.75 (s, 3H); MS m/e521 (M+1).

Example 108 MethylN-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamatedimethanesulfonic acid

The product of Example 37 was converted into the salt form.

¹H NMR (DMSO-d₆) δ 9.31 (brs, 1H), 9.02 (d, 1H), 8.56 (dd, 1H), 8.21 (d,1H), 8.05 (dd, 1H), 7.62 (d, 1H), 7.51 (m, 1H), 7.41 (m, 2H), 7.42 (m,1H), 7.33 (d, 1H), 7.17 (dd, 1H), 7.08 (d, 1H), 3.89 (s, 6H); MS m/e 505(M+1).

Example 109 MethylN-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamatemaleate

The product of Example 37 was converted into the salt form.

¹H NMR (DMSO-d₆) δ 9.21 (s, 1H), 8.95 (d, 1H), 8.57 (dd, 1H), 8.15 (d,1H), 8.00 (dd, 1H), 7.51 (m, 1H), 7.41 (m, 2H), 7.13 (d, 1H), 6.95 (d,1H), 6.86 (dd, 1H), 6.24 (s, 2H), 3.77 (s, 3H); MS m/e 505 (M+1).

Example 110N-(6-(2-((2-fluoro-5-(trifluoromethylphenyl)aminocarbonylamino)-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide

Coupling of Intermediate 12C with 2-nitro-5-bromopyridine and subsequenthydrogenation gaveN-(6-(2-amino-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide.Following the procedure for Example 1 provides the title compound.

¹H NMR (DMSO-d₆) δ 10.62 (brs, 1H), 9.92 (s, 1H), 8.67 (dd, 1H), 8.02(dd, 1H), 7.41–7.62 (m, 5H), 7.22–7.34 (m, 3H), 7.16 (brs, 2H), 6.91(dd, 1H), 5.30 (s, 2H), 2.10 (s, 3H); MS m/e 579 (M+1).

Examples 111 and 112 are prepared according to the procedure for

Example 1 using Intermediate 15B. Example 111Methyl-N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.61 (s, 1H), 8.66 (s, 1H), 8.61(d, 1H), 8.15 (d, 1H), 8.01 (dd, 1H), 7.72 (dd, 1H), 7.38 (m, 2H), 7.11(d, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 3.76 (s, 3H); MS m/e 521 (M+1).

Example 112 MethylN-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamatedihydrochloride

¹H NMR (DMSO-d₆) δ 10.35 (s, 1H), 8.76 (s, 1H), 8.29 (d, 1H), 8.24 (d,1H), 8.03 (dd, 1H), 7.63 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.16 (dd,1H), 7.11–7.07 (m, 2H), 3.88 (s, 3H); MS m/e 487 (M+1).

Example 1136-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine

The title compound was prepared according to the procedure for Example 1using Intermediate 12E, followed by acidic hydrolysis.

¹H NMR (DMSO-d₆) δ 10.69 (brs, 1H), 9.87 (brs, 1H), 8.65 (dd, 1H), 7.92(d, 1H), 7.51 (m, 2H), 7.41 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 7.18(m, 1H), 7.12 (d, 1H), 6.89 (d, 1H), 6.67 (d, 1H), 6.56 (brs, 2H), 5.23(s, 2H); MS m/e 537 (M+1).

Example 114N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide

To the suspension of the product of Example 113 in dry THF, BOC₂O (2eq.) was added at room temperature. The solution becomes clear. Afterthe reaction completion, the solvent was removed then Si-columncromathograpy was performed by CHCl₃—MeOH (1–3%) as eluent.5-(6-((2-fluloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-3-benzyl-1-tert-butoxycarbonyl-2-iminobenzimidazolidine was obtained as amorphous in good yield.

The compound (100 mg) was dissolved to pyridine, and mesylchloride wasdropped slowly (5–7 drops) to it at 0° C. After overnight stirring, themixture was quenched to the ice-water and extracted with AcOEt thensolvent was removed. To the obtained crude mixture. TFA (1 ml) wasadded. After stirring 30 min at room temperature, TFA was removed. Theobtained residue was charged to the amino-column chromatography. 5–7%MeOH—CHCl₃ eluent was used to get the title compound.

¹H NMR (DMSO-d₆) δ 11.84 (brs, 1H), 10.64 (brs, 1H), 9.92 (brs, 1H),8.66 (dd, 1H), 8.00 (brs, 1H), 7.48 (m, 4H), 7.33 (m, 5H), 7.17 (m, 1H),5.86 (dd, 1H), 5.18 (s, 2H), 2.98 (s, 3H); MS m/e 615 (M+1).

Example 115 MethylN-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzoxazol-2-yl)carbamate

To a mixture of5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyloxy)benz-3-oxazol-2-ylamine(Intermediate 11B-67.0 mg, 0.15 mmol) in pyridine (2 mL) was dropwiseadded excess amount of ClCO₂Me (ca 0.23 mL) at room temperature. Themixture was added water and stirred at room temperature overnight. Themixture was extracted with ethyl acetate. The organic layer was washedwith NaHCO₃(aq) and brine then dried over Na₂SO₄. After evaporation,residual solid was washed with MeOH and dried under reduced pressure togive the title compound (46.1 mg, 61%):

¹H NMR (DMSO-d₆) δ 9.17 (brs, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 7.49 (m,2H), 7.46 (d, 2H), 7.38 (m, 1H), 7.26 (brs, 1H), 6.99 (d, 2H), 6.92 (dd,1H), 3.70 (s, 3H); MS m/e 505 (M+1).

The following compounds (Example 116–132) were prepared according to theprocedures described for Example 1.

Example 116 MethylN-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.39 (s, 1H), 8.42 (s, 1H), 8.19(d, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.26 (t, 1H), 7.09(m, 1H), 6.83 (dd, 1H), 6.60 (dd, 1H), 3.75 (t, 3); MS m/e 502 (M+1)

Example 117 MethylN-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.17 (s, 1H), 9.04 (s, 1H), 7.58(q, 4H), 7.41 (d, 1H), 7.24 (t, 1H), 7.15 (s, 1H), 7.08 (m, 2H), 6.83(dd, 1H), 6.59 (dd, 1H), 3.75 (s, 3H); MS m/e 518 (M+1)

Example 118 MethylN-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.49 (s, 1H), 8.04 (s, 1H), 7.87(d, 1H), 7.65 (d, 1H), 7.60 (t, 1H), 7.39 (d, 1H), 7.27–7.22 (m, 2H),7.12–7.07 (m, 3H), 6.82 (dd, 1H), 6.60 (dd, 1H), 3.74 (s, 3H); MS m/e486 (M+1)

Example 119 MethylN-(5-(3-((4chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.29 (s, 1H), 9.08 (dd, 1H),8.94 (d, 1H), 7.90 (m, 1H), 7.53 (t, 1H), 7.42 (d, 1H), 7.27 (t, 1H),7.14 (d, 1H), 7.09 (m, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H);MS m/e 520 (M+1)

Example 120 MethylN-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 8.87 (s, 1H), 8.79 (s, 1H), 7.94(s, 1H), 7.41 (d, 1H), 7.31 (d, 2H), 7.23 (t, 1H), 7.11–7.03 (m, 4H),6.83 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 544 (M+1)

Example 121 MethylN-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.57 (s, 1H), 8.38 (s, 1H), 8.26(d, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 7.27 (t, 1H), 7.14 (d, 1H), 7.08(m, 2H), 7.04 (s, 1H), 6.84 (dd, 1H), 6.62 (d, 1H), 3.75 (s, 1H); MS m/e486 (M+1), 488 (M+3)

Example 122 MethylN-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.5 (brs, 2H), 9.00 (s, 1H), 8.94 (s, 1H),7.41–7.38 (m, 6H), 7.27 (t, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 7.16–7.08(m, 3H), 7.03 (d, 2H), 6.60 (dd, 1H), 3.73 (s, 3H), MS m/e 526 (M+1)

Example 123 MethylN-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 8.76 (s, 1H), 8.60 (s, 1H),7.42–7.35 (m, 5H), 7.27 (t, 1H), 7.25 (s, 1H), 7.17–7.10 (m, 2H), 7.03(d, 2H), 6.98 (d, 1H), 6.90 (d, 2H), 6.78 (dd, 1H), 6.60 (dd, 1H), 3.75(s, 3H), MS m/e 510 (M+1)

Example 124 MethylN-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 9.34 (s, 1H), 8.40 (s, 1H),7.42–7.36 (m, 3H), 7.22 (t, 1H), 7.14 (t, 1H), 7.10–7.05 (m, 4H), 7.01(d, 2H), 6.94 (td, 1H), 6.82 (m, 2H), 6.57 (d, 1H), 3.75 (s, 3H), MS m/e510 (M+1)

Example 125 MethylN-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 8.90 (s, 1H), 8.78 (s, 1H),7.43–7.40 (m, 3H), 7.36 (d, 1H), 7.34 (d, 1H), 7.22 (t, 1H), 7.16 (d,1H), 7.08 (m, 3H), 6.97–6.93 (m, 4H), 6.83 (dd, 1H), 6.55 (dd, 1H), 3.75(s, 3H), MS m/e 510 (M+1)

Example 126 MethylN-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 8.68 (s, 1H), 8.43 (s, 1H),7.40 (d, 1H), 7.32 (s, 1H), 7.21 (t, 1H), 7.11 (t, 1H), 7.08 (m, 4H),6.82 (dd, 1H), 6.55 (d, 1H), 3.75 (s, 3H), 2.79 (m, 4H), 1.98 (m, 2H),MS m/e 458 (M+1)

Example 127 MethylN-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 8.57 (s, 1H), 8.48 (s, 1H),7.41 (d, 2H), 7.37 (m, 2H), 7.11 (m, 2H), 6.99 (d, 1H), 6.90 (d, 2H),6.78 (dd, 1H), 3.75 (s, 3H), 2.80 (quint, 4H), 1.99 (m, 2H), MS m/e 458(M+1)

Example 128 MethylN-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 11.8–11.4 (brs, 2H), 9.46 (s, 1H), 8.76 (s, 1H), 7.42(d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 6.48(s, 1H), 3.74 (s, 3H), 1.29 (s, 9H); MS m/e 465 (M+1)

Example 129 MethylN-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 9.40 (s, 1H), 8.88 (s, 1H), 7.40(d, 1H), 7.25 (t, 1H), 7.13 (t, 1H), 7.07 (m, 2H), 6.82 (dd, 1H), 6.61(dd, 1H), 6.46 (s, 1H), 3.75 (s, 3H), 1.27 (s, 9H); MS m/e 465 (M+1)

Example 130 MethylN-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.2–11.2 (brs, 2H), 9.49 (s, 1H), 8.89 (s, 1H), 7.42(d, 2H), 7.40 (m, 2H), 7.20 (d, 2H), 7.11 (dd, 1H), 6.49 (s, 1H), 3.75(s, 3H), 1.28 (s, 9H); MS m/e 481 (M+1)

Example 131 MethylN-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMF-d₇) δ 12.4–11.2 (brs, 2H), 9.84 (brs, 1H), 8.22–8.20 (m,2H), 7.50 (m, 4H), 7.38 (brs, 1H), 7.36–7.34 (m, 2H), 7.22 (brs, 1H),6.92 (dd, 1H), 6.71 (m, 1H), 3.81 (s, 1H); MS m/e 502 (M+1)

Example 132 MethylN-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 9.14 (s, 1H), 8.70 (s, 1H), 8.08(d, 1H), 7.95 (d, 1H), 7.92 (d, 1H), 7.62 (d, 1H), 7.55 (m, 2H), 7.45(t, 1H), 7.41 (d, 1H), 7.62 (t, 1H), 7.16–7.14 (m, 2H), 7.10 (d, 1H),6.84 (dd, 1H), 6.59 (d, 1H), 3.75 (s, 3H); MS m/e 468 (M+1)

The compound of Example 22 was treated with2-fluoro-5-trifluoromethylphenyl, 4-chrolophenyl, andN,N-dimethylaminophenyl isocyanate in THF to give compounds of Example133, 134, and 135 respectively.

Example 1331-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

¹H NMR (DMSO-d₆) δ; 12.0–11.3 (brs, 1H), 10.7–10.1 (brs, 1H), 8.92 (s,1H), 8.63 (s, 1H), 8.46 (d, 1H), 8.39 (d, 1H), 7.29 (m, 4H), 7.22 (d,2H), 7.18–7.14 (m, 3H), 6.72 (d, 2H), 6.58 (dd, 1H), MS m/e 651 (M+1)

Example 1341-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea

¹H NMR (DMSO-d₆) δ; 9.77 (brs, 1H), 9.14 (s, 1H), 8.86 (brs, 1H), 8.62(d, 1H), 7.61 (d, 2H), 7.50 (m, 1H), 7.44 (d, 2H), 7.39 (m, 2H), 7.34(d, 2H), 6.99 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 1H), MS m/e 599 (M+1),601 (M+3)

Example 1351-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea

¹H NMR (DMSO-d₆) δ; 9.30 (brs 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d,1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.37 (brm, 2H), 7.34 (d, 2H), 7.00 (s,1H), 6.93 (d, 2H), 6.76 (d, 1H), 6.72 (d, 2H), 2.85 (s, 6H), MS m/e 608(M+1)

Example 1361-(6-(4-((4-Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea

The title compound and the next compound (Example 137) were preparedaccording to the procedures described for Example 1, using Intermediate13B.

¹H NMR (DMSO-d₆) δ; 10.57 (s, 1H), 9.15 (s, 1H), 8.84 (s, 1H), 8.11 (d,1H), 7.65–7.63 (m, 2H), 7.58 (d, 1H), 7.46 (d, 2H), 7.02 (dd, 1H), 6.98(d, 2H), 6.72 (brs, 1H), 3.15 (q, 2H), 1.46 (quint, 2H), 1.31 (sextet,2H), MS m/e 578 (M+1), 580 (M+3).

Example 1371-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea

¹H NMR (DMSO-d₆) δ; 10.58 (brs, 1H), 9.17 (s, 1H), 8.87 (s, 1H), 8.62(dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.52–7.47 (m, 1H), 7.47 (d, 2H),7.39 (m, 1H), 7.03 (dd, 1H), 6.99 (d, 2H), 6.74 (brs, 1H), 3.15 (q, 2H),1.47 (quint, 2H), 1.31 (sextet, 2H), MS m/e 562 (M+1).

Example 138N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

Intermediate 14F was treated with 23:2:75 (v/v/v) TFA/H₂O/DCM (1 mL) forca. 1 h. The solution containing the released material was collected.The resin was washed with DCM (3×, 1 mL each). The washings werecollected and combined with the original filtrate. Evaporation of thesolvent in vacuo yielded a dark sticky solid. The cleaving was repeatedtwo more times and the materials obtained after each time were combined.The crude material was dissolved in DMSO and purified with reverse-phasepreparative Gilson HPLC system to yield the desired benzimidazole.

¹H NMR (DMF-d₇) δ 10.79 (br s, 1H), 10.40 (br s, 1H), 7.64 (d, J=8.8 Hz,2H), 7.49 (br s, 1H), 7.15 (br s, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.87 (dd,J=8.6, 2.5 Hz, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.24 (s, 3H); MS m/e 407(M+1).

The following compounds (Example 139–180) were prepared in acombinatorial chemistry format using the same procedure as Example 138.In most cases, the benzimidazoles thus obtained were light colored afterHPLC purification.

Example 139N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.12 (br s, 1H), 11.61 (br s, 1H), 9.58 (br s, 1H),7.60 (d, J=8.8 Hz, 2H), 7.50 (br s, 1H), 7.39 (d, J=3.5 Hz, 1H),7.27–7.06 (m, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H),2.25 (s, 3H); MS m/e 409 (M+1).

Example 140N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.12 (br s, 1H), 11.56 (br s, 1H), 9.80 (br s, 1H),9.09 (s, 1H) 7.66 (m, 2H), 7.50 (br s, 1H), 7.19 (br s, 1H), 7.01 (d,J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.25 (s, 3H); MS m/e 410(M+1).

Example 141N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 9.61 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.50 (br s, 1H),7.16 (br s, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H),6.65 (s, 1H), 2.24 (m, 6H); MS m/e 423 (M+1).

Example 142N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 9.56 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.51 (br s, 1H),7.16 (br s, 1H), 7.04 (s, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.5,2.4 Hz, 1H), 2.35 (s, 3H), 2.25 (s, 3H); MS m/e 423 (M+1).

Example 143N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.12 (br s, 1H), 11.59 (br s, 1H), 9.70 (br s, 1H),7.65 (m, 2H), 7.50 (br s, 1H), 7.21 (br s, 1H), 7.00 (d, J=8.8 Hz, 2H),6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.62 (s, 3H), 2.25 (s, 3H); MS m/e 424(M+1).

Example 144N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.15 (br s, 1H), 11.59 (br s, 1H), 9.29 (s, 1H), 7.60(d, J=8.8 Hz, 2H), 7.53 (br s, 1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz,2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 3.00 (q, J=7.6 Hz, 2H), 2.25 (s, 3H),1.34 (t, J=7.6 Hz, 3H); MS m/e 438 (M+1).

Example 145N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 11.63 (br s, 1H), 9.28 (s, 1H), 7.59 (d, J=9.0 Hz,2H), 7.53 (br d, J=8.4 Hz, 1H), 7.18 (br s, 1H), 7.01 (d, J=9.0 Hz, 2H),6.89 (dd, J=8.6, 2.3 Hz, 1H), 2.38 (m, 1H), 2.25 (s, 3H), 1.16 (m, 2H),0.99 (m, 2H); MS m/e 450 (M+1).

Example 146N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.13 (br s, 1H), 9.50 (br s, 1H), 7.60 (d, J=8.9 Hz,2H), 7.46 (m, 1H), 7.21–7.13 (m, 1H), 7.01 (d, J=8.9 Hz, 2H), 6.89 (dd,J=8.6, 2.5 Hz, 1H), 6.68 (s, 1H), 2.25 (s, 3H), 1.27 (s, 9H); MS m/e 465(M+1).

Example 147N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.09 (br s, 1H), 11.57 (br s, 1H), 9.42 (s, 1H), 7.62(d, J=8.8 Hz, 2H), 7.51 (br s, 1H), 7.17 (br s, 1H), 7.01 (d, J=8.8 Hz,2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.25 (s, 3H), 1.42 (s, 9H); MS m/e466 (M+1).

Example 148N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.10 (br s, 1H), 11.58 (br s, 1H), 9.60 (br s, 1H),7.60 (d, J=8.8 Hz, 2H), 7.50 (br s, 1H), 7.16 (br s, 1H), 6.99 (d, J=8.8Hz, 2H), 6.87 (dd, J=8.6, 2.3 Hz, 1H), 2.24 (m, 6H), 2.13 (s, 3H); MSm/e 437 (M+1).

Example 149N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.14 (br s, 1H), 11.60 (br s, 1H), 9.67 (s, 1H), 7.73(d, J=9.1 Hz, 2H), 7.51 (br s, 1H), 7.38 (br s, 1H), 7.31–7.07 (m, 1H),7.02 (d, J=9.1 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 3.69 (m, 4H), 3.33(m, 4H), 2.25 (s, 3H); MS m/e 478 (M+1).

Example 150N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 9.85 (s, 1H), 9.43 (s, 1H), 7.59 (d, J=8.9 Hz, 2H),7.52 (br s, 1H), 7.17 (br s, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.90 (dd,J=8.6, 2.3 Hz, 1H), 6.61 (s, 1H), 4.33 (s, 2H), 3.81 (m, 2H), 3.61 (m,2H), 3.41 (s, 3H), 2.40 (s, 3H); MS m/e 481 (M+1).

Example 151N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.10 (br s, 1H), 11.04 (br s, 1H), 9.54 (s, 1H), 7.61(d, J=9.0 Hz, 2H), 7.53 (br s, 1H), 7.39 (d, J=3.5 Hz, 1H), 7.19 (br s,1H), 7.13 (d, J=3.5 Hz), 7.02 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.5Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H); MS m/e483 (M+1).

Example 152N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.23 (br s, 1H), 11.19 (br s, 1H), 9.45 (br s, 1H),9.12 (s, 1H), 7.62 (d, J=9.1 Hz, 2H), 7.54 (br d, J=8.4 Hz, 1H), 7.19(br s, 1H), 7.03 (d, J=9.1 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32(s, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H); MS m/e 484 (M+1).

Example 153N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.20 (br s, 1H), 10.95 (br s, 1H), 9.38 (s, 1H), 7.60(d, J=9.0 Hz, 2H), 7.53 (br d, J=8.2 Hz 1H), 7.18 (br s, 1H), 7.01 (d,J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.67 (s, 1H), 4.32 (s, 2H),3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.24 (s, 3H); MS m/e 497(M+1).

Example 154N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 9.35 (s, 1H), 7.59 (d, J=9.1, 2H), 7.53 (br d, J=8.4,1H), 7.18 (br s, 1H), 7.04 (app d 1H), 7.01 (d, J=9.1, 2H), 6.90 (dd,J=8.4, 2.3, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H),2.35 (app d, 3H); MS m/e 497 (M+1).

Example 155N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.23 (br s, 1H), 11.07 (br s, 1H), 9.32 (s, 1H), 7.61(d, J=9.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.20 (br s, 1H), 7.02 (d,J=9.0 Hz, 2H), 6.92 (dd, J=8.5, 2.5 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H),3.65 (m, 2H), 3.41 (s, 3H), 2.63 (s, 3H); MS m/e 498 (M+1).

Example 156N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.14 (br s, 1H), 11.16 (br s, 1H), 9.38 (s, 1H), 7.62(d, J=9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.19 (br s, 1H), 7.02 (d,J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H),3.61 (m, 2H), 3.41 (s, 3H), 3.00 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz,3H); MS m/e 512 (M+1).

Example 157N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.13 (br s, 1H), 11.24 (br s, 1H), 9.44 (s, 1H), 7.63(d, J=8.8 Hz, 2H), 7.54 (d, J=8.6, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.8Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61(m, 2H), 3.41 (s, 3H), 2.38 (m, 1H), 1.15 (m, 2H), 1.00 (m, 2H); MS m/e524 (M+1).

Example 158N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 9.54 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.55 (br d,J=8.4 Hz, 1H), 7.20 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.4,2.5 Hz, 1H), 6.69 (s, 1H), 4.33 (s, 2H), 3.82 (m, 2H), 3.61 (m, 2H),3.41 (s, 3H), 1.28 (s, 9H); MS m/e 539 (M+1).

Example 159N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.20 (br s, 1H), 11.24 (br s, 1H), 9.59 (br s, 1H),7.65 (d, J=8.9 Hz, 2H), 7.54 (br d, J=8.4 Hz, 1H), 7.19 (br s, 1H), 7.02(d, J=8.9 Hz, 2H), 6.91 (dd, J=8.4, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m,2H), 3.61 (m, 2H), 3.41 (s, 3H), 1.43 (s, 9H); MS m/e 540 (M+1).

Example 160N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 9.76 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.6,1H), 7.19 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz,1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 3.25 (q,J=7.2 Hz, 2H) 1.39 (t, J=7.3 Hz, 3H); MS m/e 544 (M+1).

Example 161N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.19 (br s, 1H), 7.77 (m, 2H), 7.52 (br s, 1H), 7.19(br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.31(s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 3.20 (t, J=7.1 Hz,2H), 1.77 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); MS m/e 588 (M+1).

Example 162N-(5-(4-((4,5-Dimetylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 9.57 (s, 1H), 7.60 (d, J=9.1 Hz, 2H), 7.53 (br d,J=8.3, 1H), 7.18 (br s, 1H), 7.00 (d, J=9.1 Hz, 2H), 6.90 (dd, J=8.3,2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H),2.24 (s, 3H), 2.14 (s, 3H); MS m/e 511 (M+1).

Example 163N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 11.22 (br s, 1H), 9.68 (s, 1H), 7.75 (d, J=9.0 Hz,2H), 7.55 (d, J=8.7 Hz, 1H), 7.38 (br s, 1H), 7.22 (br s, 1H), 7.03 (d,J=9.0 Hz, 2H), 6.93 (dd, J=8.7, 2.5 Hz, 1H), 4.33 (s, 2H), 3.82 (m, 2H),3.70 (m, 4H), 3.61 (m, 2H), 3.41 (s, 3H), 3.34 (m, 4H); MS m/e 552(M+1).

Example 164N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.80 (s, 1H), 9.38 (s, 1H), 8.00 (s, 1H), 7.59 (m,3H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.8 Hz,2H), 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 6.62 (s, 1H), 2.41 (s,3H); MS m/e 459 (M+1).

Example 165N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.56 (br s, 1H), 8.00 (s, 1H), 7.62 (d, J=8.8 Hz, 2H),7.58 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 7.20 (d,J=2.2 Hz, 1H), 7.13 (d, J=35 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd,J=8.5, 2.2 Hz, 1H), 6.75 (m, 1H); MS m/e 461 (M+1).

Example 166N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 11.95 (br s, 1H), 9.56 (br s, 1H), 9.12 (s, 1H), 8.00(s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.59 (m, 1H), 7.55 (d, J=8.6 Hz, 1H),7.21 (d, J=2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 6.93 (dd, J=8.6, 2.4 Hz,1H), 6.75 (m, 1H); MS m/e 462 (M+1).

Example 167N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.41 (s, 1H), 8.00 (s, 1H), 7.61 (d, J=9.0 Hz, 2H),7.58 (m, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.03 (d,J=9.0 Hz, 2H), 6.92 (dd, J=8.7, 2.4 Hz, 1H), 6.75 (m, 1H), 6.67 (s, 1H),2.24 (s, 3H); MS m/e 475 (M+1).

Example 168N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.48 (s, 1H), 8.00 (s, 1H), 7.61 (d, J=9.0 Hz, 2H),7.58 (d, J=3.8 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H),7.03 (m, 3H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.35 (s, 3H);MS m/e 475 (M+1).

Example 169N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 11.99 (br s, 1H), 9.45 (br s, 1H), 8.00 (s, 1H), 7.63(d, J=8.8 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H),7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz,1H), 6.75 (m, 1H), 2.62 (s, 3H); MS m/e 476 (M+1).

Example 170N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 11.93 (br s, 1H), 9.37 (br s, 1H), 8.00 (s, 1H), 7.63(d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H),7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz,1H), 6.75 (m, 1H), 3.00 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.5 Hz, 3H); MSm/e 490 (M+1).

Example 171N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 11.92 (br s, 1H), 9.42 (br s, 1H), 8.00 (s, 1H), 7.62(d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H),7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz,1H), 6.75 (m, 1H), 2.38 (m, 1H), 1.15 (m, 2H), 0.99 (m, 2H); MS m/e 502(M+1).

Example 172N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 10.60 (br s, 1H), 9.41 (br s, 1H), 8.00 (s, 1H), 7.61(d, J=8.8 Hz, 2H), 7.58 (br d, J=3.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H),7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz,1H), 6.75 (m, 1H), 6.69 (s, 1H), 1.27 (s, 9H); MS m/e 517 (M+1).

Example 173N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 11.96 (br s, 1H), 9.39 (br s, 1H), 8.00 (s, 1H), 7.64(d, J=9.1 Hz, 2H), 7.59 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.20 (d, J=2.3Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.5, 2.3 Hz, 1H), 6.75 (m,1H), 1.43 (s, 9H); MS m/e 518 (M+1).

Example 174N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 12.20 (br s, 1H), 8.00 (s, 1H), 7.75 (m, 2H), 7.58 (brs, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 3.25 (q, J=7.2 Hz,2H), 1.40 (t, J=7.2 Hz, 3H); MS m/e 522 (M+1).

Example 175N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.37 (br s, 1H), 8.00 (s, 1H), 7.60 (d, J=8.8 Hz, 2H),7.58 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.03 (d,J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H), 2.24 (s, 3H),2.14 (s, 3H); MS m/e 489 (M+1).

Example 176N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 9.69 (s, 1H), 8.00 (s, 1H), 7.76 (d, J=8.9 Hz, 2H),7.60 (br d, J=3.3 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.38 (br s, 1H), 7.23(d, J=2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 6.94 (dd, J=8.6, 2.4 Hz, 1H),6.75 (m, 1H), 3.70 (m, 4H), 3.33 (m, 4H); MS m/e 530 (M+1).

Example 177N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide

¹H NMR (DMF-d₇) δ 12.11 (br s, 1H), 11.57 (br s, 1H), 10.58 (br s, 1H),7.74 (m, 2H), 7.52 (br s, 1H), 7.30–7.07 (m, 1H), 7.00 (d, J=9.1 Hz,2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 2.95–2.72 (m, 3H), 2.24 (s, 3H); MSm/e 456 (M+1).

Example 178N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide

¹H NMR (DMF-d₇) δ 12.20 (br s, 1H), 7.77 (m, 2H), 7.52 (br s, 1H), 7.18(br s, 1H), 7.06 (d, J=9.1 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.31(s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.95–2.72 (m, 3H); MSm/e 530 (M+1).

Example 179N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

¹H NMR (DMF-d₇) δ 12.12 (br s, 1H), 9.91 (br s, 1H), 8.00 (s, 1H), 7.69(m, 2H), 7.58 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H),7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H),2.95–2.72 (m, 3H); MS m/e 508 (M+1).

Example 180N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide

This compound was prepared according to procedure for Example 138i byway of Intermediate 14F, although left-hand ring is not heteroarylic.

¹H NMR (DMF-d₇) δ 12.26 (br s, 1H), 9.23 (s, 1H), 8.57 (d, J=1.8 Hz,1H), 8.00 (s, 1H), 7.61–7.58 (m, 4H), 7.53 (d, J=8.6 Hz, 1H), 7.27 (d,J=7.8 Hz, 1H), 7.23 (br s, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (m, 1H), 2.34 (s, 3H); MSm/e 511 (M+1).

Examples 181–182 were prepared according to the procedures described forExample 1 using intermediate 3A.

Example 181 MethylN-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (br s, 2H), 9.53 (s, 1H), 8.40 (s, 1H),8.10 (dd, 1H), 7.41 (d, 1H), 7.30–7.24 (m, 3H), 7.13–7.07 (m, 3H), 6.83(dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 486 (M+1), 488 (M+3).

Example 182 MethylN-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ 12.0–11.2 (brs, 2H), 8.98 (s, 1H), 7.86 (s, 1H), 7.48(d, 1H), 7.40 (d, 1H), 7.22 (t, 1H), 7.10 (d, 1H), 7.07 (m, 2H), 7.00(t, 1H), 6.88 (d, 1H), 6.82 (dd, 1H), 3.75 (s, 3H), 2.23 (s, 3H), 2.09(s, 3H); MS m/e 446 (M+1)

Example 1831-(5-(4-((2-Fluoro-5-(trifluoromethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea

The compound of Example 22 was treated with 2,3-dimethylphenylisocyanatein THF to give the title compound.

¹H NMR (DMSO-d₆) δ; 11.5 (brs, 1H), 10.4 (brs, 1H), 9.6 (brs, 1H), 9.13(s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.68 (d, 1H), 7.50 (t, 1H), 7.44(d, 2H), 7.38 (m, 2H), 7.08 (t, 1H), 7.02 (brs, 1H), 6.94 (d, 2H), 6.94(d, 1H), 6.79 (dd, 1H), 2.28 (s, 3H), 2.22 (s, 3H), MS m/e 593 (M+1)

The following compounds (Example 184–186) are synthesized according tothe similar procedure for Example 1 using corresponding isothiocyanatein lieu of isocyanate.

Example 184 MethylN-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 9.89 (s, 1H), 9.85 (s, 1H),7.70 (t, 1H), 7.42–7.32 (m, 5H), 7.16 (d, 1H), 7.06 (d, 1H), 6.92 (d,2H), 6.81 (dd, 1H), 3.75 (s, 3H); MS m/e 468 (M+1), 470 (M+3).

Example 185 MethylN-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 9.73 (s, 1H), 9.71 (s, 1H),7.40 (m, 1H), 7.39 (d, 2), 7.22 (t, 1H), 7.18 (s, 1H), 7.05 (s, 1H),7.01 (d, 1H), 6.91 (d, 2), 6.80 (dd, 1H), 6.70 (dd, 1H), 3.75 (s, 3H),3.74 (s, 3H); MS m/e 464 (M+1).

Example 186 MethylN-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate

¹H NMR (DMSO-d₆) δ; 12.0–11.2 (brs, 2H), 9.95 (s, 1H), 9.92 (s, 1H),7.95 (s, 1H), 7.75 (d, 1H), 7.55 (t, 1H), 7.44 (d, 1H), 7.39 (m, 1H),7.38 (d, 2H), 7.06 (s, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 3.75 (s, 3H);MS m/e 502 (M+1).

Biological Data

TIE-2Enzyme Assay (TIE2-E)

The TIE-2 enzyme assay used the LANCE method (Wallac) and GST-TIE2,baculovirus expressed recombinant constructs of the intracellulardomains of human TIE2 (amino acids 762–1104, GenBank Accession # L06139)tagged by GST). The method measured the ability of the purified enzymesto catalyse the transfer of the γ-phosphate from ATP onto tyrosineresidues in a biotinylated synthetic peptide, D1-15(biotin-C6-LEARLVAYEGWVAGKKKamide). This peptide phosphorylation wasdetected using the following procedure: for enzyme preactivation,GST-TIE2 was incubated for 30 mins at room temperature with 2 mM ATP, 5mM MgCl₂ and 12.5 mM DTT in 22.5 mM HEPES buffer (pH7.4). PreactivatedGST-TIE2 was incubated for 30 mins at room temperature in 96 well plateswith 1 μM D1-15 peptide, 80 uM ATP, 10 mM MgCl₂, 0.1 mg/ml BSA and thetest compound (diluted from a 10 mM stock in DMSO, final DMSOconcentration was 2.4%) in 1 mM HEPES (pH7.4). The reaction was stoppedby the addition of EDTA (final concentration 45 mM). Streptavidinlinked-APC (allophycocyanin, Molecular Probe) and Europium-labeledanti-phosphorylated tyrosine antibody (Wallac) were then added at thefinal concentration of 17 μg/well and 2.1 μg/well, respectively. The APCsignal was measured using an ARVO multilabel counter. (Wallac BertholdJapan). The percent inhibition of activity was calculated relative toblank control wells. The concentration of test compound that inhibits50% of activity (IC₅₀) was interpolated using nonlinear regression(Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where“K” was equal to the IC₅₀. The IC₅₀ values were converted to pIC₅₀values, i.e., −log IC₅₀ in Molar concentration. The results arerepresented in Table 1 below.

TIE-2 Autophosphorylation Assay (TIE2-C)

The TIE-2 autophosphorylation assay used an ELISA method and a TIE2intracellular domain/c-fms extracellular domain (TIE2/c-fms) chimericprotein expressing mouse 3T3 cells. This assay measured theautophosphorylation level of TIE2 protein expressed in cells. The cellswere cultured in high glucose DMEM (Sigma) containing 10% serum at 37°C. in a humidified 10% CO₂, 90% air incubator. The test compound(diluted from a 10 mM stock in DMSO, final DMSO concentration was 0.1%)was incubated with TIE2/c-fms expressing cells for 1 hr in serum freeDMEM in 96 well plates followed by the activation of TIE2/c-fms receptorusing c-fms ligand, MCSF (macrophage colony stimulating factor). Theculture media was removed by aspiration and the cells incubated for atleast 30 mins on ice with lysis buffer containing 137 mM NaCl, 2 mMEDTA, 10% glycerol, 0.09 ml sodium ortho vanadate and complete proteaseinhibitor cocktail (Roche) in 20 mM Tris-HCl (pH8.0). The cell extractswere transferred into Rat anti-c-fms antibody coated 96 well plates andincubated for 12 hrs at 4° C. The extracts were removed by aspirationand the plate was incubated with biotinylated anti-phosphotyrosineantibody, PT66 (Sigma) and then with HRP (HorseradishPeroxidase)-labeled streptavidin (PIERCE). The optical density at 450 nmderived from HRP catalyzed TMB was measured with an ARVO multilabelcounter. (Wallac Berthold Japan). The percent inhibition of activity wascalculated relative to blank control wells. The concentration of testcompound that inhibits 50% of activity (IC₅₀) was interpolated usingnonlinear regression (Levernberg-Marquardt) and the equation, y=Vmax(1−x/(K+x))+Y2, where “K” was equal to the IC₅₀. The IC₅₀ values wereconverted to pIC₅₀ values, i.e., −log IC₅₀ in Molar concentration. Theresults are represented in Table 1 below.

Tie2 Fluorescence Polarization Kinase Activity Assay: (TIE2-FP)

Activation of Recombinant Tie2 Activation:

Recombinant GST-Tie2 was activated by incubating the enzyme in 20 mMTris-HCl, pH 7.5, 12 mM MgCl₂, 100 mM NaCl, 20 μM sodium vanidate, 1 mMDTT and 300 μM ATP at room temperature for 2 hours. The activationmixture was then passed through a NAP-25 desalting column (PharmaciaBiotech cat. no. 17-0852-02) to remove the free ATP. The activatedenzyme was stored as aliquots at −80° C. in 20 mM Tris-HCl, pH 7.5 and100 mM NaCl.

Assay Conditions:

The final assay conditions were 50 mM HEPES, pH 7.5, 5% DMSO (whenscreening compounds), 200 μM ATP, 5 mM MgCl₂, 1 mM DTT, 50 μM sodiumvanidate, 1 nM activated enzyme, and 200 μM peptide. IC₅₀'s of compoundswere measured under subsaturating ATP (200 μM) and varing concentrationsof activated Tie2 and peptide substrate (RFWKYEFWR-OH; MW 1873 Da, TFAsalt). Panvera Antiphosphotyrosine antibody (Cat#P2840) and PTK GreenTracer (Cat#P2842) were used to detect the phosphorylated peptide.Polarization was measured on a TECAN Polarion in 138-second cycles for30 minutes at room temperature. IC₅₀'s were then determined from the %polarization using normal calculation methods. Results are indicatedbelow.

VEGF-R2 Enzyme Assay (VEGF-E)

The VEGF enzyme assay used the LANCE method (Wallac) and GST-VEGFR2,baculovirus expressed recombinant constructs of the intracellulardomains of human TIE2 tagged by GST. The method measured the ability ofthe purified enzymes to catalyse the transfer of the γ-phosphate fromATP onto tyrosine residues in a biotinylated synthetic peptide,(biotin-aminohexyl-EEEEYFELVAKKKK-NH₂). This peptide phosphorylation wasdetected using the following procedure: GST-VEGFR2 was incubated for40–60 mins at room temperature with 75 μM ATP, 5 mM MgCl₂, 0.1 mM DTT,0.1 mg/mL BSA and the test compound (diluted from a 10 mM stock in DMSOfor desired concentration) in 100 mM HEPES buffer. The reaction wasstopped by the addition of EDTA (final concentration 50 mM).Streptavidin linked-APC (allophycocyanin, Molecular Probe) andEuropium-labeled anti-phosphorylated tyrosine antibody (Wallac) werethen added at the final concentration of 15 nM and 1 nM, respectively.The APC signal was measured using an ARVO multilabel counter (WallacBerthold, Japan). The percent inhibition of activity was calculatedrelative to blank control wells. The concentration of test compound thatinhibits 50% of activity (IC₅₀) was interpolated using nonlinearregression (Levernberg-Marquardt) and the equation, y=Vmax(1−x/(K+x))+Y2, where “K” was equal to the IC₅₀. The IC₅₀ values wereconverted to pIC₅₀ values, i.e., −log IC₅₀ in Molar concentration. Theresults are represented in Table 1 below.

VFGF-driven Cellular Proliferation Assay: BrdU Incorporation Assay(VEGF-C)

Human umbilical cord endothelial cells (HUVEC, Clonetics, CC2519) werepassaged in Type I collagen-coated 100-mm petridishes in EGM-MV medium(Clonetics, CC3125) at 37° C. in a humidified 5% CO₂, 95% air incubator.(HUVEC passaged more than 6 times in vitro were discarded and notsubjected to assaying.) The cells were harvested using trypsin/EDTA,counted using a haemocytometer and plated at 5000 cells/well in a TypeI-collagen coated 96-well plate (Becton Dickinson, 354407) in M199medium (Gibco BRL, 12340-030) containing 5% FBS (Hyclone, A 1115-L) andgentamicin (at 50 μg/ml, Gibco BRL). After incubation overnight at 37°C., the media were replaced with 100 μl of M199 serum-free mediumcontaining compounds at various concentrations with 0.6% DMSO andgentamicin. The compounds were diluted in serum-free M199 medium from 10mM stock solutions prepared in 100% DMSO. After a 30 min incubation at37° C., the cells were fed with 100 μl of serum-free M199 mediumcontaining gentamicin, 0.2% culture-grade bovine serum albumin (BSA,Sigma A1993) and 20 ng/ml of VEGF (R&D systems, 293-VE) or 0.6 ng/ml ofbasic FGF (R&D systems, 233-FB), and cultured at 37° C. for another 24h. The cells were pulsed with bromodeoxyuridine (BrdU at 10 μM inserum-free M199) at 37° C. for an additional 24 h. The incorporation ofBrdU into the proliferating HUVEC were analyzed using BrdU CellProliferation ELISA (Roche Molecular Biochemicals, 1647229) according tothe manufacturer's protocols. The optical density at 450 nm was measuredwith a multilabel counter (ARVO SX, Wallac). The percent inhibition ofcell growth was calculated relative to blank control wells. Theconcentration of test compound that inhibits 50% of cell growth (IC₅₀)was interpolated using nonlinear regression (Levernberg-Marquardt) andthe equation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC₅₀.The IC₅₀, values were converted to pIC₅₀ values, i.e., −log IC₅₀ inMolar concentration. The results are represented in Table 1 below.

Test compounds are employed in free or salt form.

TABLE I Ex. No TIE2-E TIE2-C VEGF-E VEGF-C  1 +++ ++ +++ −  2 +++ ++++++ +  3 ++ +++ −  4 +++ + ++ −  5 ++ +++ + −  6 +++ + −  7 +++ − −  8+++ +++ −  9 +++ +++ +++ −  10 +++ +++ +++ +++  11 +++ ++ +++ −  12 +++++ + −  13 +++ ++ ++ −  14 ++ ++ +++ ++  15 +++ +++ +++ ++  16 +++ ++++++  17 +++ +++ +++ +++  18 +++ +++ +++ +++  19 +++ +++ +++ −  20 +++ +++++  21 +++ +++ −  22 +++ + +++ +  23 +++ +++ ++  24 +++ ++ +++ −  25+++ +++ +++ +++  26 +++ ++ +++ ++  27 +++ +++ +++ ++  28 +++ +++ +++ ++ 29 +++ +++ +++ ++  30 +++ +++ +++ ++  31 +++ +++ +++ +++  32 +++ ++ + 33 +++ +++ +++ +++  34 +++ +++ +++ −  35 +++ ++ +++ +  36 +++ +++ −  37+++ +++ +++ −  38 +++ +++ +++ −  39 ++ ++ ++  40 +++ +++ +++ −  41 ++++++ +++ −  42 +++ +++ +++ ++  43 +++ +++ +++ +  44 +++ ++ +++ −  45 ++++++ +++ −  46 +++ +++ +++ −  47 +++ +++ +++ −  48 +++ +++ +++ −  49 ++++ +++ −  50 +++ +++ +++ ++  51 +++ +++ +++ −  52 +++ ++ +++  55 +++ ++++++ −  56 ++ +++ +++ −  57 +++ ++  58 +++  59 +++  60 +++  61 +++  62 ++++  63 − +++  64 +++ +++ +++ +++  65 +++ +++ +++ −  68 +++ +++ +++ +++ 69 +++ +++ +++ ++  70 +++ ++ +++ +  71 +++ ++ +++ +  72 +++ +++ +++ + 73 ++ ++ +++  74 +++ +++ +++ −  75 ++ +++ +++ −  76 +++ +++ −  77 ++++++ +++ ++  78 +++  79 ++ ++  80 +++ +++ +++ +++  81 +++ +++ +++ −  87+++ +++ +++ ++  88 +++ +++ +++ +++  89 +++ +++ +++ ++  90 +++ + +++  91+++ +++ +++ −  92 +++ +++ +++ +++  93 +++ +++ +++ +  94 +++ +++ +++ + 95 +++ ++ +++  96 +++ +++ +++ ++  97 +++ +++ +++ +++  98 +++ +++ +++ ++ 99 +++ ++ +++ 100 +++ +++ +++ 101 +++ +++ +++ +++ 102 +++ +++ +++ +++103 +++ +++ +++ + 104 ++ ++ +++ 105 ++ + +++ 106 ++ ++ +++ 107 +++ ++ ++110 +++ ++ ++ 111 +++ +++ +++ − 112 ++ ++ ++ 113 +++ 115 +++ +++ +++ +++116 +++ 117 +++ 118 ++ 119 +++ 120 +++ 121 ++ 123 ++ 124 +++ 125 +++ 127+++ 128 +++ 129 +++ 130 +++ 133 +++ 134 +++ 136 +++ 137 +++   146* +++++   151* + ++   152* + +   153* + ++   155* + ++   156* ++ +++   158*++ +++   159* +++ +++ 163 + 184 + + +++ 185 ++ + 186 + ++ +++ + = pIC₅₀of 5.0–6.0; ++ = pIC₅₀ of 6.0–7.0; +++ = pIC₅₀ of > 7.0; − = a negativeor inconclusive result; blank = not tested *Tie-2 activities runutilizing Tie2-FP assay described above.

1. A compound of Formula (I):

or a salt or solvate, thereof: wherein: E is unsubstituted heteroaryl,or heteroaryl substituted with R¹, or heteroaryl substituted by R¹ andR², or R¹ and R² together with the atoms of E to which they are attachedform a cycloalkyl, aryl, or heterocyclic ring fused to E; A is aryl,heteroaryl, or heterocyclic; X is S, O, S(O)₂, S(O), C(H)₂, C(H)(OH), orC(O); Z is O or S; p is 0 or 1; q is 0 or 1; the dotted line bonds “---”attached to Q and N′ represent a single bond or a double bond whereinwhen q is 0 the dotted line bond “---” attached to Q is a single bondand the dotted line bond attached to N′ is a double bond, and when q is1 the dotted line bond “---” attached to Q is a double bond and thedotted line bond attached to N′ is a single bond; and the dotted linewithin the 6 membered ring containing D, M, and T represents appropriatearomatic bonds; D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p), wherein pis 0 and q is 1; or D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p),wherein p is 1 and q is 0; R¹ is C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl,heteroaryl, heterocyclic, halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy,aralkyl, aralkoxy, aryloxy, C₁–C₆ alkylsulfanyl, C₁–C₆haloalkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, —NO₂,—NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, or cyanoalkyl; R² ishydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, aryl, heteroaryl, heterocyclic,aralkyl, aralkoxy, aryloxy, halogen, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy,C₁–C₆ alkylsulfanyl, C₁–C₆ haloalkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆alkylsulfonyl, oxo, hydroxy, —NO₂, —NR⁴R⁵, —C(O)OR⁶, —CN, —C(O)NR⁴R⁵,—S(O)₂NR⁴R⁵, or cyanoalkyl; R³ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl,aralkoxy, heteroaryl, heterocyclic, —RR⁶, —RNR⁴R⁵, —C(O) R⁶, —C(O)NR⁴R⁵,—C(O)OR⁶, —C(O)RO R⁶, —C(O)RC(O)OR⁶, —C(O)R R⁶, —C(O)RR′R⁶,—C(O)ROR′OR″O R⁶, —C(O)ROR′O R⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O) R⁶,—C(O)RNR⁴C(O)OR⁶, —C(O)ORNR⁴R⁵, —S(O)₂ R⁶, or —S(O)₂NR⁴R⁵; or R³ isC₁–C₆ alkylene or C₁–C₆ alkylene substituted with oxo, and is linkedtogether with the nitrogen to which it is attached and to one of thebenzimidazole nitrogens to form a heterocylic compound fused to thebenzimidazole; R, R′, and R″, are each independently selected from C₁–C₆alkylene, arylene, heteroarylene, C₃–C₇cycloalkylene, orheterocyclylene; R′″ is C₁–C₆ alkyl, aryl, heteroaryl, aralkyl, C₃–C₇cycloalkyl, or heterocyclic; R⁴ and R⁵ are each independently selectedfrom hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, aryl, heteroaryl, aralkyl,heterocyclic, C₃–C₇ cycloalkyl, —C(O)OR⁶, —C(O)NR′″R′″, —C(O)NR′″H,—C(O)NH₂, or —S(O)₂NR′″R′″; R⁶ is hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C₃–C₇ cycloalkyl;R⁷ is hydrogen, C₁–C₆ alkyl, —S(O)₂ R⁶, —RNR⁴R⁵, —RR⁶, or aralkyl; andR⁸ is hydrogen or halogen.
 2. A compound as claimed in claim 1, whereinthe compound of formula (I) is a compound of formula (IV):

wherein E is, heteroaryl substituted with R¹, or heteroaryl substitutedwith R¹ and R², or a salt or solvate thereof.
 3. A compound as claimedin claim 1, wherein the group A is linked to the side chain —NHC(Z)NHEand to the linker group X of the benzimidazole core through a (-1,3-) ora (-1,4-) linkage.
 4. A compound as claimed in claim 1, wherein R¹ isC₁–C₆ alkyl, aryloxy, C₁–C₆ alkoxy, C₁–C₆ haloalkyl, C₁–C₆haloalkylsulfanyl, C₁–C₆ alkylsulfanyl, —C(O)OR⁶, halogen, —CN, or —NO₂.5. A compound as claimed in claim 1, wherein R² is hydrogen, halogen,C₁–C₆ alkyl, C₁–C₆ alkoxy, or C₁–C₆ haloalkyl.
 6. A compound as claimedin claim 1, wherein D is CH, T is CR⁸, M is C and Q is N(R⁷)_(p),wherein p is 0, q is 1, R⁷ is hydrogen, methyl, or S(O)₂R⁶.
 7. Acompound as claimed in claim 1, wherein D is CH, T is CR⁸, wherein R⁸ ishydrogen or —Br, M is C and Q is N(R⁷)_(p), wherein p is 1, q is 0, R⁷is hydrogen, methyl, —S(O)₂R⁶, —RNR⁴R⁵, —RR⁶ or aralkyl.
 8. A compoundas claimed in claim 1, wherein D is CH, T is CR⁸, wherein R⁸ ishydrogen, M is C and Q is N(R⁷)_(p), wherein either p or q is 0, theother is 1 and R⁷ is hydrogen.
 9. A compound as claimed in claim 1,wherein R³ is —C(O) R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)RO R⁶, —C(O)RC(O)OR⁶,—C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O)R⁶,—C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 10. A compound as claimed inclaim 1, wherein A is phenyl; X is O; Z is O; R¹ is C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ haloalkyl, or —NO₂; R² is hydrogen, halogen, C₁–C₆ alkyl,or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)ROR⁶,—C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 11. A compoundas claimed in claim 1, wherein A is phenyl; X is S; Z is O; R¹ is C₁–C₆alkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkyl, or —NO₂; R² is hydrogen, halogen,C₁–C₆ alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 12. A compoundas claimed in claim 1, wherein A is pyridyl; X is O; Z is O; R¹ is C₁–C₆alkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkyl, or —NO₂; R² is hydrogen, halogen,C₁–C₆ alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 13. A compoundas claimed in claim 1, wherein A is pyridyl; X is S; Z is O; R¹ is C₁₋₆alkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkyl, or —NO₂; R² is hydrogen, halogen,C₁–C₆ alkyl, or C₁–C₆ alkoxy; and R³ is —C(O)R⁶, —C(O)NR⁴R⁵, —C(O)OR⁶,—C(O)ROR⁶, —C(O)RC(O)OR⁶, —C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵,—C(O)RNR⁴C(O)R⁶, —C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 14. A compoundas claimed in claim 2, wherein the compound is a compound of formula(IV) where E is heteroaryl substituted with R¹, or heteroarylsubstituted with R¹ and R²; A is phenyl; X is O; Z is O; R¹ is C₁–C₆alkyl, aryl, C₃–C₇ cycloalkyl, heterocyclyl, C₁–C₆ haloalkyl, or C₁–C₆alkylsulfanyl; R² is hydrogen, halogen, C₁–C₆ alkyl, or C₁–C₆ haloalkyl;and R³ is —C(O)R, —C(O)NR⁴R⁵, —C(O)OR⁶, —C(O)ROR⁶, —C(O)RC(O)OR⁶,—C(O)ROR′OR″OR⁶, —C(O)ROR′OR⁶, —C(O)RNR⁴R⁵, —C(O)RNR⁴C(O)R⁶,—C(O)RNR⁴C(O)OR⁶, —SO₂R⁶, or —SO₂NR⁴R⁵.
 15. A compound as claimed inclaim 1, selected from the group consisting of: methylN-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;methylN-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;methylN-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;methylN-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;N-(5-(4-((5-methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((4-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((4-tert-butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-tert-butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((4,5-dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((4-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((4tert-butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-tert-butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((4,5-dimetylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;N-(5-(4-((5-methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((4-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-fury)formamide;N-(5-(4-((5-ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-cycloproyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((4-tert-butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-tert-butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((4,5-dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;N-(5-(4-((5-methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;N-(5-(4-((5-methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;andN-(5-(4-((5-methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;or a salt or solvate thereof.
 16. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound as claimedin claim 1, or a salt or solvate, thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 17. Apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound as claimed in claim 2, or a salt or solvate thereofand one or more of pharmaceutically acceptable carriers, diluents andexcipients.
 18. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound as claimed in claim 15,or a salt or solvate thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.